Download Zentrum für Infektionsforschung Research Center for Infectious

Zentrum für
Infektionsforschung
Research Center for
Infectious Diseases
Wissenschaftlicher Jahresbericht für 2005/2006
Annual Scientific Report 2005/2006
Zentrum für Infektionsforschung
Research Center for Infectious Diseases
der Universität Würzburg
of the University of Wuerzburg
Röntgenring 11
97070 Würzburg
Germany
Phone ++49-(0)931-312064, 312575
Fax ++49-(0)931-312578
e-mail: [email protected]
http://www.infektionsforschung.uni-wuerzburg.de
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3. Die Institutionen des Zentrums
für Infektionsforschung
3. Institutions of the Research
Center for Infectious Diseases
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3. Die Institutionen des Zentrums für Infektionsforschung
3.1 Institut für Virologie und
Immunbiologie, Lehrstuhl für
Virologie
3.1 Institute for Virology and
Immunobiology - Chair of
Virology
Der Lehrstuhl für Virologie im Institut für
Virologie und Immunologie betreut das
Universitätsklinikum in allen virusdiagnostischen Fragen und bekommt darüber
hinaus zahlreiche Einsendungen aus ganz
Deutschland und dem benachbarten Ausland zur Abklärung viraler Infektionen des
Zentralen Nervensystems, eine Domäne,
auf die unser Lehrstuhl seit langem spezialisiert ist. Daneben werden in dieser Abteilung klinisch-virologische Fragestellungen bearbeitet, wozu z.B. die Abklärung des
pathogenen Werts „neuer“ Viren gehört.
Neben der Virusdiagnostik ist aber, was
die Anzahl der zum großen Teil dritmittelfinanzierten Mitarbeiter anbetrifft, die Grund-
Axel Rethwilm
3. August 1959
Academic Education/Degrees:
1978-1984 Study of Medicine University of Freiburg, Germany
1984
Registration as M.D.
1985
Acceptance of M.D. thesis Institute for Virology,
University of Freiburg
1985-1987 Postdoc training, German Cancer Research Center,
Heidelberg, Germany
1987-1989 Postdoc training Institute for Virology and Immunobiology,
University of Würzburg, Germany
1989-1993 Research Associate Institute for Virology and Immunobiology,
University of Würzburg
1992
"Habilitation“, Faculty of Medicine, University of Würzburg
1993
Assistant Professor in Virology, University of Würzburg
1995
Associate Professor in Virology, University of Würzburg
1998-2003 Full Professor and Chairman Institute for Virology,
Medical Faculty Technical University Dresden
2003
Approval as Specialist in Board of Physicians, Saxonia
Microbiology and Epidemiology of Infectious Diseases
2003
Full Professor and Co-Chairman, Institute for Virology
and Immunobiology, University of Würzburg
Prof. Dr. med. Axel Rethwilm
Institut für Virologie und Immunbiologie
Universität Würzburg
Versbacher Str. 7
97078 Würzburg
Tel.: ++49 (0)931 201-49554
Fax: ++49 (0)931 201-49553
[email protected]
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lagenforschung, die in derzeit 8 Arbeitsgruppen organisiert ist, der Schwerpunkt
des Instituts. Auch hier dominieren Erreger, die ZNS-Infektionen hervorrufen sowie
Retroviren. Die einzelnen Arbeitsgruppen
stellen sich im folgenden hier vor:
In the group of Benedikt Weißbrich 30-35
thousand clinical samples are processed
each year. Furthermore, a variety of clinicalvirological questions are being addressed.
Due to the start of allogeneic stem cell
transplantation at the university clinic and
because of new therapeutic options for the
treatment of viral infections, the importance
and number of viral load measurements
and resistance tests has further increased
during the last two years. Besides the
routine testing of clinical samples, new
respiratory viruses are being studied in
cooperation with the children’s hospital of
the university clinic. The human bocavirus,
which was first described in 2005 by a
Swedish group, has been detected in 11%
of nasopharyngeal samples of children
who were hospitalised for acute respiratory
diseases. There were a strikingly high
number of coinfections with other respiratory viruses among the children who were
positive for bocavirus DNA. Further studies
including bocavirus antibody determinations are currently ongoing in order to
elucidate if bocavirus is a „real pathogen“
or if it is „just an innocent bystander“.
Besides bocavirus, the recently described
coronaviruses NL63 and HKU-1 have also
been detected in the nasopharyngeal
aspirates. Additional studies have included
the molecular epidemiology and clinical
correlation of these virus infections as well
as the evaluation of routine diagnostic tools
for their detection.
Tina Dörries and her team concentrate on
the pathogenesis of human polyomavirus
infections. Human polyomavirus infections
are wide spread in the world population.
The virus persists lifelong and is generally
asymptomatic. However, in immunosuppressive states as induced by HIV-1
infections, lymphoproliferative diseases or
immunosuppressive therapies related with
transplantation, the two virus species JCV
and BKV are associated with central
nervous system (CNS) diseases in HIV
patients, severe nephropathies after
kidney transplantation and haemorrhagic
cystitis after bone marrow transplantation.
In each of these diseases the persistent
infection can be activated to severe viral
infections with considerable cell damage
and symptomatic disease. Whereas in
symptomatic disease stages no therapeutical effect could be achieved, it is
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discussed that early diagnosis of viral
activation and therapeutic intervention
might have a beneficial effect on the
disease process. The aim is therefore to
characterize accessible target cells of human polyomavirus infections and their viral activation state in healthy and immunosuppressed individuals. Lately we were
able to characterize peripheral blood cells
as target cells for JCV and BKV infection in
general. Subpopulations affected included
lymphocytes and monocytic cell types. Risk
group patients have a higher rate of affected
circulating cells, but in healthy as well as
in patients at risk viral infection is latent
and only rarely single genes are expressed. This suggests that peripheral
blood cells are carrier of viral genomic
information and might be involved in the
dissemination and enhancement of infection in immunosuppressed patients. At
present the load of infected cells appears
to be correlated with the immunosuppressive state and thus may be a valuable
factor for early diagnosis of polyomavirusassociated activation processes.
The group of Eleni Koutsilieri examines
the mechanisms by which the CNS adapts
to injury and disease of diverse aetiology.
Of particular concern are the interactions
between the various cell types in the brain
such as neurones, astrocytes and microglia. In one set of studies, investigations
on the neurobiology of HIV-dementia are
being performed. Research activities in
this field, besides cell biology, are extended to rhesus macaques and humans in
a multi-disciplinary effort that combines
clinical evaluation, neuroimaging, as well
as neurochemical, virological, immunological and neuropathological methods.
The molecular mechanisms, which underlie exacerbation of SIV encephalopathy by
the neurotransmitter dopamine, is one of
the main targets of the research. The group
could demonstrate that drugs that are used
in the clinic to increase dopamine availability in the brain as well as drugs of abuse
dramatically accelerate SIV infection in the
brain, exacerbate neuropathological
features and enhance viral load. There is
evidence that activated microglia alter
functional elements of the glutamatergic
synapses in specific brain regions, rendering them susceptible for excitotoxic death.
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On the other hand, the group tries to answer
the question of how great is the involvement
of microglia activation as an aetiological
factor for HIV-induced neurodegeneration
compared to the HIV-proteins themselves
in a cell model of microglia and neuronal
cell types expressing the HIV-Tat protein.
Moreover, together with the group of Carsten Scheller, gene therapeutic approaches for the treatment of various
neuropsychiatric diseases are being
developed. Using AAV vector-mediated
expression of small interfering RNAs
(siRNAs), the groups study knockdown of
genes involved in the pathogenesis of
hereditary Alzheimer’s disease. Foamyvirus vector-mediated expression of neurotrophic factors is being studied for the
treatment of Parkinson Disease using the
generation of transgenic haematopoietic
stem cells. Moreover, the groups have
studied latent infection of HIV in T-cells and
its reactivation by CpG-oligodeoxynucleotides for the development of an HIV
reactivation therapy.
The group of Jürgen Schneider-Schaulies
investigates the interaction of surface
glycoproteins of morbilliviruses (e.g
measles and canine, seal, or dolphin
distemper viruses) with their speciesspecific cellular receptors. These interactions are critically involved in the cellular
tropism of a given virus, the viral spread in
the host, the ability to cross the blood-brainbarrier and, consequently, they critically
determine the viral pathogenesis. Besides
a general haemorrhagic infection, these
viruses can also cause lethal CNS disease. In this context, the infection of
endothelial and epithelial cells and a
directional transport of viruses or viral
protein through these cells appears to play
an important role. The interferon-gammainducible enzyme indoleamine 2,3-dioxygenase (IDO) could be identified in
endothelial and epithelial cells as an
important mediator of antiviral activity. The
antiviral activity, which is most likely based
on tryptophane depletion, is directed
against a variety of pathogens, among them
herpes simplex virus (HSV-1) and measles
virus (MV). Antibodies against the cellular
tetraspanin CD9 inhibit the canine distemper virus (CDV)-induced cell fusion and
possibly virus release. We found that this
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3. Die Institutionen des Zentrums für Infektionsforschung
antiviral activity is mediated via the
haemagglutinin of CDV. As a further
possibly therapeutically usable antiviral
mechanism the aplicabilty of siRNA
against MV was investigated. An effective
inhibition of virus replication was achieved
with siRNAs directed against transcripts
of the components of the viral replicative
complex. Interestingly, siRNA against the
matrix protein-mRNA stimulated the
replication complex. Finally, the group
succeeded to establish a mouse animal
model of a persistent MV infection of the
CNS using recombinant MV (Figure 1).
This model will allow a statistically confirmed analysis of the role of the immune
system and possible therapeutic regiments in the CNS.
In spite of the availability of an efficient live
vaccine, acute MV infections are still
associated with 800,000 lethal cases
worldwide, particularly among children in
developing countries. In industrialized
countries, major complications include
pneumonia and encephalitis, which usually do not take a lethal course. This, however,
does not apply to the subacute sclerosing
pan-encephalitis (SSPE), an inevitably
lethal disease, which develops with a
frequency of 1 per 10,000 cases of acute
measles and results from a persistent MVCNS infection after a clinically silent
incubation period of several years. The
majority of measles-associated fatalities,
however, is due to a generalized transient
immunosuppression caused by MV, which
favours the establishment of secondary
infections and aggravates their clinical
course. MV-induced immunosuppression
is characterized by a marked lymphopenia
and the inability of blood mononuclear cells
to expand in response to polyclonal or
antigen-specific stimulation in vitro. Although MV has a tropism for lympho/
monocytic cells, the frequency of infected
cells is extremely low, indicating that
immunosuppression is a consequence of
mechanisms that are not directly related to
the infection itself. These mechanisms are
investigated in the group of Sibylle Schneider-Schaulies. Functional consequences
of MV contact dependent interference with
activation of the PI3/Akt kinase pathway in
T cells have been a major focus of interest.
As a result of this inhibition, T cells were
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found to be severely compromised in their
ability to reorganise the cortical actin
cytoskeleton as important for polarisation
towards and formation of functional immunological synapses with dendritic cells
(DCs) and rather revealed an almost
complete collapse of microvillar extensions. Moreover, again by impeding
PI3K activity, MV is able to regulate the activity
of splicing accessory proteins and thereby
the efficiency of alternative splicing of
cellular transcripts in T cells. A second
focus is the analysis of the interaction of
MV with DCs. Entry into these cells is
enhanced by the ability of MV to bind to DCSIGN, yet they restrict late stages of the viral replication cycle. To analyse these,
basic studies on intracellular trafficking of
the MV M protein, which is essential for
assembly and morphogenesis, were
performed in fully permissive fibroblast cell
lines.
The groups of Michael Klein and Eckhard
Flechsig investigate the mechanisms for
the neuroinvasion of prions and the molecular events leading to the neurodegeneration in prion diseases. Current
studies address the questions whether the
expression of the cellular prion protein
(PrPC) in the peripheral nervous system and
the immune system are required for efficient
prion transport. Furthermore, immune
therapeutic strategies are currently developed for protection against prion
diseases and several studies including our
own work could demonstrate that delivery
of PrP-specific antibodies represents a
promising approach for prevention. Moreover, we are evaluating the underlying
mechanisms of neurodegeneration responsible for the destruction of the nervous
system. Recently, we could show that
oxidative stress parameters in the brain of
prion-infected mice precede the clinical
stages, whereas a depletion of the serotonin neurotransmitter transporter does not
alter the susceptibility to mouse scrapie.
Marc Kirschner and his team investigate
the role of soluble, trimer-stabilized and
properly cleaved HIV-1 gp140 Envelope glycoproteins (Env) in vaccine development.
Trimeric HIV-1 Env are now being evaluated
instead of monomeric gp120 as vaccine
antigens because they mimic more closely
the spikes expressed on the surface of
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virions. Thus, it can be argued that Env
trimers have a more native structure than
gp120 and may be superior at raising
neutralizing antibodies. In order to make
trimeric Env proteins for structural and
immunization studies we introduce an
engineered disulfide bond between the
gp120 and gp41ECTO subunits to stabilize
their interaction, thus allowing the expression of a fully cleaved gp140 protein
(SOS gp140). An additional substitution
(I559P) within gp41 ECTO creates a more
stable, trimeric Env protein, designated as
SOSIP gp140. Recombinant expressed
SOSIP gp140 can be purified to homogeneity by affinity as well as size exclusion
chromatography. We investigate the
antigenic structure and immunogenicity of
trimeric Env proteins from different HIV-1
subtypes as well as immunization strategies with novel immune response
modifiers, e.g. the Toll Like Receptor 7
agonist Imiquimod, for optimal antigen
presentation in pre-clinical tests.
In a different approach the team attempts
to develop assays to screen for alternative
anti-HIV compounds that inhibit the interaction of the cellular antiviral protein
Apobec3G with the HIV-1 viral infectivity
factor Vif. When the cytidin-deaminase
Apobec3G is packed into virions it leads to
G to A hypermutations within the viral
genome, therefore rendering it inactive. The
Vif protein is expressed from the viral
genome and interacts with Apobec3G
leading to its degradation by the ubiquitin
protein degradation pathway. We are
developing a screening assay based on
Fluorescence Resonance Energy Transfer (FRET) as well as Bimolecular Fluorescence Compensation (BiFC) to detect
substances inhibiting the Apobec-Vif
interaction and therefore preventing Apobec3G degradation. We use Apobec and
Vif tagged with the green fluorescent protein
(GFP) as well as its yellow (YFP) and cyan
(CFP) derivatives to measure BiFC or FRET
signals in the presence of potential antiviral compounds.
In the group of Jochen Bodem different
projects on primate retroviruses are
pursued. Besides studying new foamy
viruses from the New World monkey Ateles
and from equines the post-transcriptional
regulation of nuclear RNA export in foamy
viruses is investigated. Although of highly
complex genetic structure, foamy viruses
have so been regarded to lack any mechanism regulating nuclear RNA export.
Therefore these kinds of investigations are
in terms of a comparative Retrovirology of
high importance. In addition, novel mechanisms how HIV acquires resistance to antiretroviral drugs are studied. In particular, a
multi-resistant HIV protease has been
characterized and the crystal structure is
under investigation in collaboration with
part-ners in Hungary and the Czech Republic. Furthermore, we recently obtained
the first German full-length sequence of a
Chikungunya virus from an outbreak in
Mauritius. A German tourist imported this
virus to Würzburg when returning from the
island.
Figure 1:
Recombinant measles virus-positive
neuron in infected mouse brain.
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3. Die Institutionen des Zentrums für Infektionsforschung
3.2. Institut für Virologie und
Immunbiologie, Lehrstuhl für
Immunologie
Am Lehrstuhl für Immunologie werden in
vivo und in vitro Modelle der Reifung und
Aktivierung von Lymphozyten untersucht.
Genetisch modifizierte Maus- und Rattenlinien dienen der Aufklärung der Funktion
einzelner molekularer Komponenten des
Immunsystems. Monoklonale Antikörper
gegen Rezeptormoleküle werden zur Manipulation von Immunantworten gegen
Modellantigene und Krankheitserreger eingesetzt.
In der Arbeitsgruppe von PD Dr. Ingolf
Berberich wird die Regulation von Überleben bzw. programmiertem Zelltod in B-Zellen untersucht. Der B-Zellantigenrezeptor
(BCR) bestimmt, ob eine B-Zelle auto-
Thomas Hünig
04. März 1950
1968-1974
1974
1978
1979-1981
1981-1985
1984
1985-1990
since 1990
Studies in Biology at the Universities of Würzburg and Heidelberg
Diploma in Biology
Awarded degree of Dr. of Sciences (Dr. rer. nat.) „with honors“
by the University of Würzburg
Postdoc with Dr. M. J. Bevan, MIT. Research on: Ontogeny of the
T-cell repertoire in chimeric and athymic mice
Head of a research group of the SFB 105, University of Würzurg.
Research on: Activation and specificity of T-cells
Habilitation Immunology, University of Würzburg
Group Leader, Gene Center/MPI Munich. Research on: Antigen
receptors and cell interaction molecules of T-lymphocytes
Chairman of the Department of Immunology at the Institute for
Virology and Immunobiology, University of Würzburg.
Research on: Rat T-cell specificity, selection, maturation and
activation, γ/δ T-cells, IL-2/IL-2R system, CD28
Prof. Dr. Thomas Hünig
Institut für Virologie und Immunbiologie
Universität Würzburg
Versbacher Str. 7
97078 Würzburg
Tel.: ++49(0)931-201-49951
Fax:++49(0)931-201-49243
[email protected]
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reaktiv und damit schädlich ist, oder ob sie
für die Erkennung von „fremd“, z.B. von infektiösen Erregern, zur Verfügung steht.
Dementsprechend signalisiert der BCR in
gerade erst entstandenen B-Zellen den
Zelltod. Rettungssignale können über das
Zelloberflächenmolekül CD40 gegeben
werden, an das Helfer-T-Zellen mit einem
zellständigen Liganden andocken können.
Wichtig für die „Verarbeitung“ pro- und antiapoptotische Signale in B-Zellen ist u. a.
das anti-apoptotische Bcl-2 Familienmitglied A1; das Protein wird hinsichtlich seiner Regulation und Funktionsweise inten-
siv untersucht. Ferner untersucht die Gruppe die differentielle Regulation des „Master-Transkriptionsfaktors“ in B-Zellen
Blimp-1.
Die Gruppen von Prof. Thomas Herrmann,
Dr. Thomas Kerkau, Prof. Holger Reichardt
und Prof. Thomas Hünig bearbeiten verschiedene Aspekte der T-Zellbiologie in
den Tiermodellen der Ratte und Maus.
Prof. Herrmann und seine Mitarbeiter arbeiten an der Identifizierung und funktionellen Charakterisierung „seltener“ Subpopulationen von T Lymphozyten, insbesondere der γ/δ T Zellen sowie der NKT
Zellen, denen eine wichtige Rolle bei der
unmittelbaren Infektabwehr pathogener
Keime zugeschrieben werden. Von besonderem Interesse sind dabei die Antigenrezeptoren und Antigen-präsentierenden
Moleküle auf den Zielzellen. Hier gelang
die erstmalige Identifizierung des CDR2
der T-Zellrezeptor-β-Kette als für die
Antigenerkennung von NKT Zellen wichtiger Bereich. Weiterhin wurde ein neues
nicht-polymorphes Ratten-MHC Klasse II
Molekül mit ungewöhnlichen Superantigen-präsentierenden Eigenschaften entdeckt. Die Arbeiten zur Aktivierung humaner Vγ9Vδ2
T Zellen durch Rezeptoren des natürlichen
Immunsystems (NKG2D und TLR) sowie
zur Erkennung bakterieller und synthetischer Liganden durch den Vγ9Vδ2 T-Zellantigenrezeptor wurden fortgesetzt, während die Arbeiten zur perinatalen Transmission von Toxplasma gondii abgeschlossen
wurden.
In der Gruppe von Prof. Reichardt werden
transgene Ratten- und Mausmodelle zur
Analyse der intrathymischen T-Zelldifferenzierung und peripheren T-Zellfunktion
entwickelt. Bisher gelang es zehn verschiedene Linien transgener Ratten, u.a.
Notch1IC-transgene sowie eGFP-transgene („grüne“) Tiere zu generieren und in
verschiedenen Analysen einzusetzen. Die
Notch-transgenen Ratten zeigen nicht nur
eine interessante Modifikation des T-Zellreifungsprogramms im Thymus, sondern
entwickeln auch spontan Lymphome, die
als Modell für entsprechende Erkrankun-
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3. Institutions of the Research Center for Infectious Diseases
gen des Menschen dienen können. Die
eGFP-transgenen Ratten hingegen haben
sich als wertvoll für die Analyse der Pathogenese und Therapie von muri-nen Modellen der Multiplen Sklerose erwiesen. Ein
weiterer Schwerpunkt der Arbeitsgruppe ist
die Funktion von Glukokortikoidrezeptoren
in der Kontrolle des Überlebens von Lymphozyten sowei der Modulation entzündlicher Prozesse.
Dr. Kerkau und seine Mitarbeiter suchen
nach neuen Strategien zur Immuntherapie
der Graft-versus-host-disease (GvHD), einer schwerwiegenden Komplikation nach
allogener Knochenmarkstransplantation.
Die Immunzellen im allogenen Knochenmarks-Transplantat attackieren und schädigen die Organe des Patienten und lösen
so die GvHD aus. Im Zentrum des Interesses einer Immuntherapie der GvHD stehen regulatorische T-Zellen, die unter bestimmten experimentellen Bedingungen
die Aktivierung der die GvHD auslösenden
alloreaktiven T-Zellen unterdrücken können. Mit Hilfe neuartiger monoklonaler Antikörper sollen die regulatorischen T-Zellen aktiviert und expandiert und infolgedessen die Aktivität der GvHD moduliert werden.
Prof. Hünigs Gruppe interessiert sich für
den kostimulatorischen T-Zellrezeptor
CD28 und seinen Gegenspieler, CTLA-4
(CD152). Diese beiden Rezeptoren sind
entscheidend an der Regulation von TZellaktivierung und ihrer Unterdrückung bei
Autoimmunität oder überschießenden
Immunantworten beteiligt. Mit Hilfe aktivierender und blockierender monoklonaler
Antikörper untersuchen wir die Signaltransduktion sowie das therapeutische
Potential einer Interferenz mit der CD28vermittelten Kostimulation bzw. einer
CD28-vermittelten polyklonalen T-Zellaktivierung. Dabei stehen Infektions- und
Autoimmunitätsmodelle im Vordergrund.
Von besonderer Bedeutung ist ein neues
Modell für Multiple Sklerose, bei dem das
Hühnereiweiß als „neo-Autoantigen“ in einem bestimmten Zelltyp des Zentralnervensystems, den für die Isolierung der
Nervenstränge verantwortlichen Oligodendrozyten, exprimiert wird. In diesem
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Modell lösen CD8 T-Zellen eine Zerstörung
der Oligodendrozyten aus, was mit einem
Funktionsverlust von Nervenzellen und
entsprechenden motorischen Störungen
einhergeht. Die Bedeutung der CD8 T-Zellen in der menschlichen Erkrankung ist
schon länger bekannt, konnte aber bisher
nicht in einem geeigneten Tiermodell untersucht werden.
3.2 Institute for Virology and
Immunobiology - Chair of
Immunology
At the chair of immunology, in vivo and in
vitro models of lymphocyte differentiation
and activation are being studied. Gene-
Thomas Kerkau
28. April 1959
1965-1970 Grundschule Oerlenbach/Germany
1970-1978 Schönborn-Gymnasium Münnerstadt/Germany, Abitur 1978
1978-1980 National service
University education:
1980-1986 Medical school at the University of Würzburg/Germany
1986
Approbation
Academic career:
Since 1987 Scientific assistant at the Institute for Virology and Immunobiology,
University of Würzburg
1991
Medical doctorate (Dr. med.) awarded by the University of Würzburg
Since 1991 Head of the laboratory of immune diagnostics at the University of
Würzburg
tically modified mouse and rat strains are
used to elucidate the function of individual
molecular components of the immune
system. Furthermore, monoclonal antibodies to receptor molecules are being
developed and used to manipulate the
immune response against model antigens and infectious agents.
The group of PD Dr. Ingolf Berberich
focuses on the regulation of cell survival
versus programmed cell death in B-cells.
The B-cell antigen receptor (BCR) dictates
whether a B-cell is autoreactive or whether
it is potentially useful in the recognition of
foreign invaders. Accordingly, BCR ligation
in newly generated B-cells is interpreted
as autoreactivity and hence mediates cell
death. Rescue signals can be provided via
the cell surface molecule CD40, through
which helper T-cells can signal with a cell
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3. Die Institutionen des Zentrums für Infektionsforschung
surface bound ligand. At the level of
intracellular propagation of these signals,
the analysis of the anti-apoptotic Bcl-1
protein A1 has taken center stage in the
group’s research efforts. In addition, the
group is interested in the differential
expression of the master transcription factor
Blimp-1 in B cells.
The groups of Prof. Dr. Thomas Herrmann,
Dr. Thomas Kerkau, Prof. Holger Reichardt
and Prof. Dr. Thomas Hünig work on
various aspects of T-cell biology in rats and
mice.
Ingolf Berberich
11. Februar 1958
1977 Abitur at the Burghardt Gymnasium, Buchen
1979 Studies in Biology at the Universities of Würzburg
1986 Diploma in Biology
1990 Degree of PhD (Dr. rer. nat.) by the University of Würzburg
1993-1995 Postdoc with Dr. Eduard A. Clark, University of Washington, Seattle,
USA. Research on: CD40 signaling in B lymphocytes
since 1995 Groupleader at the Department of Immunology at the Institute for
Virology and Immunobiology, University of Würzburg. Research on: Pro
liferation, Differentiati on and Apoptosis of B Lymphocytes
2002 Habilitation Immunology, University of Würzburg
Prof. Herrmann and his group work on
identification and functional characterization of rare subsets of T-lymphocytes,
especially γ/δ – and NKT cells, which are
supposed to play an important role in first
line defense against pathogenic microorganisms and immunoregulation. The
group´s special interests are antigen
receptors and antigen presenting molecules on target cells. They showed that
the CDR2 region of the T-cell antigen
receptor β-chain contributes to antigen
recognition by NKT cells and identified a
new non-polymorphic rat MHC class II with
unusual superantigen-presenting properties. The work on the activation of human Vγ9Vδ2 T cells by innate immune
receptors (NKG2D and TLRs) and the
recognition of bacterial and synthetic
ligands by the Vγ9Vδ2 T-cell antigen
receptor has been continued, and that on
the perinatal transmission of T. gondii has
been completed.
In the group of Prof. Reichardt, transgenic
rat and mouse models are being developed for the analysis of intrathymic T-cell
differentiation and function of peripheral Tcells. So far ten different transgenic rat
strains were generated, amongst them
Notch1IC-transgenic and eGFP-transgenic (“green“) animals, and applied to
biomedical reserach. Notch1IC-transgenic rats do not only display an interesting
modification of T-cell maturation in the
thymus, but also spontaneously develop
T-cell lymphomas, providing a useful
model for the study of Notch1-associated
tumors in humans. In contrast, the eGFPtransgenic rats are a valuable tool to study
the pathogenesis and therapy of multiple
sclerosis in murine models. Another focus
of research in the group is the function of
glucocorticoid receptors in the control of
lymphocyte survival and the modulation of
inflammatory processes.
Dr. Kerkau and his team develop novel
strategies for the treatment of Graft-versushost-disease (GvHD), a frequent complication following allogeneic bone marrow transplantation. GvHD is induced by
donor-derived alloreactive T-cells attacking
tissues and organs of the patient. Re-
1977 Abitur at the Burghardt Gymnasium, Buchen
1979 Studies in Biology at the Universities of Würzburg
1986 Diploma in Biology
1990 Degree of PhD (Dr. rer. nat.) by the University of Würzburg
1993-1995 Postdoc with Dr. Eduard A. Clark, University of Washington, Seattle,
USA. Research on: CD40 signaling in B lymphocytes
since 1995 Groupleader at the Department of Immunology at the Institute for Virology
and Immunobiology, University of Würzburg. Research on: Proliferation,
Differentiation and Apoptosis of B Lymphocytes
2002 Habilitation Immunology, University of Würzburg
Holger Reichardt
01. März 1969
ZINFbericht-final.P65
36
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
gulatory T cells have been shown to
modulate disease activity but in most
cases they are not powerful enough to
prevent GvHD. Therefore, novel monoclonal antibodies which are able to activate
regulatory T cells are now being assessed
for their potential to keep GvHD in check.
Prof. Hünig’s group is interested in the Tcell costimulatory receptor CD28 and in its
counter-regulator, CTLA-4 (CD152). These two receptors play a key role in the
control of T-cell activation and its suppression in situations of autoimmunity or
excessive immune responses (hypersensitivity). With the help of activating and
blocking monoclonal antibodies to CD28,
we are studying signal transduction by
CD28, and the therapeutic potential of
interfering with CD28-mediated costimulation or promoting CD28 mediated polyclonal T-cell activation. In these studies,
we focus on models of infection and
autoimmunity. Of particular importance is
a new model of MS, in which ovalbumin is
expressed as a neo-autoantigen in a
certain cell type of the central nervous
system, the oligodendrocytes responsible
for the insulation of exons. In this model,
CD8 T-cells trigger the destruction of
oligodendrocytes, leading to a loss of
function of the neurons and corresponding
motoric disturbances. While the role of
CD8 T-cells in human MS has been
suspected for a long time, so far, however,
animal models in which their contributiion
can be studied have been lacking.
1977 Abitur at Landschulheim am Solling, Holzminden,
1977-1985 Studies in Biology at University of Göttingen and
Freie Universität Berlin
1985 Diploma in Biology.
1989 Awarded degree of PhD (Dr. rer. nat.) „with honors“ by the
Freie Universität Berlin
1989-1991 Postdoc with H.R MacDonald, LICR, Epalinges/Lausanne.
Research on: MHC class II binding and CD8 T cell activation
by superantigens
1992-2000 Postdoc and assistant professor at the Institute for Virology
and Immunobiology, University of Würzburg
1996 Habilitation in Immunology, University of Würzburg.
2001 Associate Professor for Immunogenetics at the Institute for Virology and
Immunobiology, University of Würzburg. Research on rat T cell repertoire
and recognition of (super)antigens, γ/δ T cells and NKT cells, rat model
of perinatal and congenital toxoplasmosis
ZINFbericht-final.P65
37
23.04.2007, 14:49
Thomas Herrmann
24. Februar 1959
37
38
3. Die Institutionen des Zentrums für Infektionsforschung
3.3 Institut für Hygiene und
Mikrobiologie
Die Hauptaufgaben des Institut für Hygiene und Mikrobiologie sind die Labordiagnostik von Infektionskrankheiten, die
durch Bakterien, Pilze und Parasiten
hervorgerufen werden, die Beratung der
behandelnden Ärzte bei der Diagnostik,
Therapie und Prävention von Infektionskrankheiten, die Forschung über Infektionskrankheiten und ihre Erreger, die
Krankenhaushygiene und die Lehre für
Studierende der Medizin, Zahmedizin und
anderer Fachrichtungen. Im Bereich der
Krankenversorgung verfügt das Institut
zusätzlich zum vollen Spektrum der Routineuntersuchungen über ein umfangreiches Repertoire an molekularbiologischen Spezialuntersuchungsverfahren. Ferner gehört die Erarbeitung von
Strategien zur Vermeidung von Kranken-
Matthias Frosch
24. Februar 1960
Prof. Dr. Matthias Frosch
Institut für Hygiene und Microbiologie
Universität Würzburg
Josef-Schneider-Str.2
97080 Würzburg
Tel.: ++49 (0)931 201-46160
Fax:++49 (0)931 201-46445
[email protected]
www.hygiene.uni-wuerzburg.de/
hwww.meningococcus.de/
www.echinococcus.de/
ZINFbericht-final.P65
38
hausinfektionen und die Überwachung
der Krankenhaushygiene zu den Aufgaben in der Krankenversorgung. Jährlich
werden ca. 85.000 diagnostische Untersuchungen zu diesen Fragestellungen
durchgeführt. Im Zentrum der Forschungsaktivitäten des Instituts stehen die molekularen Ursachen der Entstehung von
Infektionskrankheiten. Mit Methoden der
Molekulargenetik, Zellbiologie, Immunologie und Genomforschung werden grundlegende Fragen der Pathogenität verschiedener bakterieller und parasitärer
Krankheitserreger bearbeitet, aber auch
Konzepte entwickelt, die neue Möglichkeiten zur Therapie und Vorbeugung
von Infektionskrankheiten eröffnen sollen.
Am Institut wurde Anfang 2002 vom
Bundesministerium für Gesundheit das
Nationale Referenzzentrum für Meningokokken (NRZM) eingerichtet. Zu den
Aufgaben des NRZM gehört die Identi-
1979-1986 Studies in medicine, University of Mainz
1986 MD thesis in Medical Microbiology (Prof. D. Bitter-Suermann),
Institute of Medical Microbiology, Mainz
1986-1987 Post-Doc, Max-Planck Institut of Biology (Prof. T.F. Meyer), Tübingen
1987-1994 Group Leader, Institute of Medical Microbiology, Medical School
Hannover
1992 Habilitation Medical Microbiology, Medical School Hannover
1994-1996 Hermann- and Lilly Schilling Professorship, Medical School Hannover
since 1996 Professor (C4) of Hygiene and Microbiology, University of Würzburg
Selected Awards:
1986 Heinz-Maier-Leibnitz Award (Deutsche Forschungsgemeinschaft),
1986 Tancré Award (Medical Faculty, University of Mainz)
1993 Research Award (Deutsche Gesellschaft für Pädiatrische Infektiologie)
1995 bioMerieux Diagnostik Award (Deutsche Gesellschaft f. Hygiene und
Mikrobiologie)
1998 Research Award, Deutsche Gesellschaft für Hygiene und Mikrobiologie
2003 Offer of a C4-professorship for Hygiene and Medical Microbiology,
University of Heidelberg
since 2006 Dean ofthe MedicalFaculty, University of Würzburg
Project Management:
2001- Co-ordinator „Implication of meningococcal epidemiology and population
biology on public health in Europe“, EU Biomed
2001- Co-ordinator „Genomforschung an pathogenen Bakterien“ BMBF
Functions in Societies:
1999-2004 Secretary of the German Society of Hygiene and Microbiology (DGHM)
2001- Member of the scientific board of the association Berufsverband der Ärzte
für Mikrobiologie und Infektionsepidemiologie
2004-2006 President of the DGHM
Since 2005 President of the European Meningococcal Disease Society (EMGM)
Editorial work:
since 1999 Editorial Board „International Journal of Medical Microbiology“
since 2002 Editor „Journal of Infection“
since 2004 Editorial Board „Infection and Immunity“
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
fizierung und serologische bzw. molekularbiologische Typisierung von Meningokokken, Beratung zum Fallmanagement von Meningokokkenerkrankungen und die Beratung von Gesundheitsämtern bei der epidemiologischen Untersuchung gehäuft auftretender Meningokokkenerkrankungen. Mit diesem Aufgabenkatalog ist das Institut in eine europaweite Gruppe von Referenzzentren, die
„European Monitoring Group on Meningococci“ eingebunden. Ferner ist am
Institut für Hygiene und Mikrobiologie das
Konsiliarlabor für Echinokokkose im
Auftrag des Robert-Koch Instituts angesiedelt. Das Institut bestimmt Serumantikörper gegen Echinococcus multilocularis und Echinococcus granulosus
und berät zu Fragen der Diagnostik,
Therapie, Prävention und Epidemiologie
der Echinokokkose.
3.3 Institute of Hygiene and
Microbiology
The main tasks of the Institute for Hygiene
and Microbiology are (i) laboratory diagnosis of infectious diseases caused by
bacteria, fungi and parasites; (ii) advisory
functions for physicians in diagnosis,
therapy and prevention of infectious
diseases; (ii) basic research on infectious
diseases and their causative agents; (iv)
hospital hygiene, and (v) teaching and
training for students of medicine, dentistry
and several other biomedical disciplines.
Concerning patients care, the institute not
only employs the full spectrum of routine
diagnosis but also a comprehensive
repertoire of special molecular techniques
for pathogen identification and characterization. Furthermore, the development
of avoidance strategies of hospital infections and hospital hygiene surveillance
form part of this area of expertise. Altogether, about 85.000 diagnostic examinations per year are carried out in these
fields of activity. Central to the research
activities of the institute are the molecular
mechanisms associated with infectious
diseases. Basic questions on the pathogenicity of bacterial and parasitic organisms are investigated by means of an array
modern methodology of molecular biology,
ZINFbericht-final.P65
39
cell biology, immunology and genomics.
Furthermore, concepts are being developed to allow for novel strategies of
treatment and prevention in infectious
disease.
In 2002, the Federal Ministry of Health set
up the National Reference Center for
Meningococci (NRZM) at the institute.
Among the tasks of the NRZM are the
identification as well as the serological
and molecular biological typing of meningococci, and an advisory function for
public health departments concerning epidemiological investigations of frequently
occurring meningococci infections. In
fulfilling these tasks, the institute forms
part of a group of reference centers
distributed all over Europe, the „European
Monitoring Group on Meningococci“.
Furthermore, by appointment of the
Robert-Koch-Institute, the consultant
laboratory for echinococcosis has been
set up at the institute. The respective tasks
comprise serological investigations on
infections caused by the cestodes Echinococcus multilocularis and E. granulosus,
and advisory functions concerning diagnosis, therapy, prevention and epidemiology of echinococcosis.
Research foci
Comparative pathogenomics of Neisseria
meningitidis (Christoph Schoen and Matthias Frosch)
Neisseria meningitidis (the meningococcus) colonises the human nasopharynx
of up to 30% of the population and most
isolates from healthy carriers are considered as non-pathogenic. Only a small
number of strains belonging to so called
Fig.1: Immunogold-Labeling of plasminogen
recruited to the surface of Neisseria meningitidis
23.04.2007, 14:49
39
40
3. Die Institutionen des Zentrums für Infektionsforschung
hypervirulent lineages are found to cause
the majority of invasive diseases. A basic
assumption is that meningococcal virulence is genetically determined by pathogenicity factors encoded in the bacterial
chromosome. However, these are at
present only partly understood. Therefore,
in collaboration with the teams of Dr. P
Brandt (MWG Biotech, Ebersberg, Germany) and Dr. A. Goesmann (Centre for
Biotechnology, BeBiTec, University of Bielefeld, Germany) the whole-genome
sequence of three non-pathogenic meningococcal carrier isolates were sequenced and annotated by funding of the
Network of Competence PathGenoMik.
Based on the publicly available genome
data from the three representative hypervirulent meningococcal isolates in silico
whole genome comparisons revealed that,
Ulrich Vogel
27.November 1964
Academic career:
1984-1990 Studies of Medicine at the University of Würzburg
1991-1992 AiP at the Institute for Hygiene and Microbiology Würzburg
1992-1996 Research Fellow at the Medical School Hannover
1996-2001 Group leader at the Institute for Hygiene and Microbiology Würzburg
2000
Habilitation in Medical Microbiology
2000
Promotional award of the German Society for Hygiene and
Microbiology (DGHM)
since 2001 Deputy Professor at the Institute for Hygiene and Microbiology
(temporary engagement)
Scientific Co-workers:
Dr. univ. Johannes Elias
Dr. med. Giuseppe Valenza
Dr. rer. nat. Kerstin Hubert
apl. Prof. Dr. med. Ulrich Vogel
Institut für Hygiene und Microbiologie
Josef-Schneider-Str. 2
97080 Würzburg
Tel.++49 (0)931 201-46802
Fax ++49 (0)931 201-46445
[email protected]
ZINFbericht-final.P65
40
with the exception of genes involved in
capsule synthesis almost all other genes
so far considered to be virulence associated were also present in at least one of
the non-virulent strains. Furthermore, a
putative core patho-genome comprising
approximately 40 genes could be defined
that is shared by all the hypervirulent strains
and absent in the non-virulent carrier
strains. Currently, on the basis of these
results a meningococcal microarray is
designed comprising known virulence
associated genes and the putative pathogenome. In close cooperation with Prof. Dr.
U. Vogel (National Reference Centre for
Meningococci, Institute for Hygiene and
Microbiology, University of Würzburg,
Germany) this meningococcal pathoarray
will consecutively be used for the comparative genome hybridisation of genomic
DNA from 200 representative hypervirulent
meningococcal isolates currently circulating in Germany and 100 representative carriage isolates obtained recently
from a carriage study in Bavaria.
Recognition of meningococci by the human immune system
(Oliver Kurzai and Matthias Frosch):
Focus is laid on the molecular basis of the
interaction between N. meningitidis and
human dendritic cells, which represent a
major regulatory entity of human immunity.
Surface structures of meningococci are
tested with regard to their potential for
activation of dendritic cells. Scavenger
receptor A family has been identified as the
major receptors mediating uptake of N.
meningitidis by dendritic cells. In close
cooperation with the team of Dr. Schoen
further experiments are targeted towards
elucidation of the molecular basis of different virulence in meningococcal lineages.
Recognition of pathogenic fungi by the immune system
(Oliver Kurzai)
Pathogenic fungi, especially Candida spp.
and Aspergillus spp. are a major threat for
immunocompromised patients. The prognosis and putcome of these infections are
bad and the immune responses evoked
have not yet been understood. In cooperation with the team of PD Dr. Loeffler
(Medizinische Klinik und Poliklinik II) the
activation of human granulocytes by Aspergillus and Candida is investigated. Surface
structures responsible for recognition of
fungi by the innate immune system will be
identified. Furthermore, the contribution of
different grnaulocyte effector mechanisms
to inactivation of the fungi will be assessed.
Pathogenesis and genomics of meningococcal disease
(A. Schubert-Unkmeir)
An important feature of Neisseria meningitidis is its ability to invade the meninges.
This requires that bacteria cross the bloodcerebrospinal fluid (B-CSF) barrier, which
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
is one of the tightest barriers of the body.
The major focus of our group is the
investigation about the molecular analysis
of the interaction of N. meningitidis with
human brain endothelial cells (HBMEC).
We have shown that meningococci specifically invade brain endothelial cells rather than the peripheral endothelial cells.
To further improve our understanding of
Neisseria-host cell interactions, we have
analysed gene expression profiles in
infected HBMEC using cDNA microarrays.
We are currently analysing some of these
genes to determine their relevance in the
specific invasion process.
Infection epidemiology, bacterial capsule
genetics, and complex bacterial populations (Ulrich Vogel, Heike Claus)
The working group follows several research topics related to the population
biology of meningococci and the genetics
of capsular polysaccharide synthesis. In
addition, it provides the institute with a
research infrastructure for typing of pathogens in hospital hygiene, and for the molecular epidemiology of meningococcal
infection in Germany, which is dealt with at
the National Reference Laboratory for
Meningococci (head: Matthias Frosch,
deputy head: Ulrich Vogel).
At the meningococcal reference laboratory,
a computer based early warning system
for the detection of spatio-temporal clusters
of meningococcal disease has been
established. Precise and highly discriminatory DNA-sequence-based typing has
been indispensable for this effort. To
enhance laboratory surveillance in Germany, the collaboration with the Robert
Koch-Institute and several Federal State
authorities has been intensified. In collaboration with Jürgen Albert (Würzburg)
and Dag Harmsen (Münster), a geographical information system has been set
up to facilitate the analysis of the spatiotemporal distribution of specific finetypes
(www.episcangis.org).
As methicillin-resistant Staphylococcus
aureus and vancomycin-resistant enterococci are of increasing importance
for hospital hygiene, molecular typing
schemes have been established and
validated for these pathogens. Of note, we
could report of the combined use of MLST,
ZINFbericht-final.P65
41
MLVA, and PFGE for epidemiologically
defined enterococci. Ulrich Vogel is partner
of the European SeqNet network for
sequence based typing (www.seqnet.org).
The genetics of meningococcal capsule
synthesis traditionally has been a focus of
the research activities at the institute. In the
past two years we have resolved the genetic
basis for different substrate specificities of
closely related meningococcal polysaccharide polymerases. Furthermore, in
collaboration with Martina Mühlenhoff
(Hannover), the function, structure and
population biology of polysialic acid Oacetyltransferases in E. coli K1 and N.
meningitidis have been studied.
Finally, our group has followed two projects
related to oral biofilms and complex
bacterial populations. Firstly, we have
established a meningococcal biofilm
model in collaboration with Søren Molin
1983-1988
1992
1993-1995
1996-2003
2001
2004
Awards:
1993-95
2003
2004
41
Joachim Reidl
09. November 1961
Studies in biology, Diploma, University of Konstanz
Dr. rer. nat.; Doctoral-thesis with Prof. W. Boos, Lehrstuhl Molecular
Microbiology, University of Konstanz
Post-Doc at Harvard Medical School (Prof. J.J. Mekalanos), Boston,
USA
Junior group leader, Centre for Infectious Diseases, University of
Würzburg
Habilitation; Venia legendi microbiology, University of Würzburg
C3-Professorship for microbial physiology and cell biology,
Institute for Hygiene and Microbiology, University of Würzburg
Post.-Doc.-Fellowship of the „Studienstiftung des Deutschen
Volkes“
Offer for a C3-professorship for molecular parodontology, University
of Münster
Offer for a professorship for microbiology, University Graz, Austria
(Lyngby, Denmark) and analysed the impact
of pili and pilus associated proteins on biofilm structure. The model will be used in
future to address the yet poorly understood
carrier state of meningococci. Secondly,
biofilms associated with periodontal
disease have been studied by molecular
ecology methods. A study in collaboration
with the Department for Periodontology
(Ulrich Schlagenhauf) has recently been
finalized, which investigated the extent of
changes to the bacterial composition
induced by mechanical and antibiotic
treatment in subjects with aggressive
periodontitis.
23.04.2007, 14:49
Prof. Dr. Joachim Reidl
Institut für Hygiene und Microbiologie
Universität Würzburg
Josef-Schneider-Str.2
97080 Würzburg
Tel. ++49 (0)931 201-46159
Fax ++49 (0)931 201-46445
[email protected]
42
3. Die Institutionen des Zentrums für Infektionsforschung
Host-adaptation and virulence of Haemophilus influenzae and Vibrio cholerae
(Joachim Reidl)
Microbes are able to achieve high levels of
adaptation in response to environmental
conditions. For example, pathogenic
bacteria are able to respond to changing
host conditions, immune response, and
antibiotic action. We are interested in
investigating molecular pathogenesis and
our emphasis lies on bacterial adaptation
and physiology of Haemophilus influenzae
and Vibrio cholerae in response to environmental and host conditions. H. influenzae represents a class of bacteria, such
as Helicobacter, Streptococcus, Menigococcus, Borrelia, Treponema, Mycoplasma
etc. all of which have adapted/evolved highly
specific to their host environment, i.e. the
humans. Whereas V. cholerae belongs to
bacteria which can be found as free living
Klaus Brehm
04. September 1964
1984-1990
1995
Studies in Biology, Diploma, University of Würzburg
Dr. rer. nat.; Doctoral thesis with Prof. J. Kreft and Prof. Werner
Goebel, Chair of Microbiology University of Würzburg
Topic: Virulence factors of Listeria monocytogenes
1995-1997 Post-Doc at the Complutense University in Madrid, Spain, with
Prof. Jose-Antonio Vazquez-Boland
Topic: Virulence gene regulation in Listeria monocytogenes
1997-2004 Research group leader at the Institute of Hygiene and
Microbiology,
University of Würzburg (Prof. Dr. M. Frosch); Medical Faculty
Topic: Molecular biology of Echinococcus multilocularis
2004
Habilitation; Venia legendi in Medical Microbiology;
University of Würzburg
2004
C3-Professorship for Medical Parasitology, Institute of Hygiene
and Microbiology, University of Würzburg
Functions, Awards:
1995
PhD thesis ‘summa cum laude’
1996
Awardwinner of the ‘Commemorative Foundation for Science of
Lower Franconia’
since 2004 Chairman of the informal WHO working group Echinococcus basic
biology
since 2006 Advisory board, whole genome sequencing project Taenia solium
Senior Scientist:
Dr. Markus Spiliotis
Prof. Dr. Klaus Brehm
Institut für Hygiene und Mikrobiologie
Universität Würzburg
Josef-Schneider-Strasse 2
97080 Würzburg
Tel.: +49(0)931-201-46168
Fax.: +49(0)931-201-46445
[email protected]
ZINFbericht-final.P65
42
cells in the environment, such as other
pathogens, for example Escherichia,
Yersinia, and Salmonella. Therefore, V.
cholerae harbours a broad repertoire of
physiological attributes. Our research
focuses on specialized catabolic/metabolic
pathways and cell surface-exposed structures, which facilitate optimal adaptation,
Fig. 2. Developing protoscolex (early stage) at
the germinal layer of the Echinococcus multilocularis metacestode
colonization, persistence, and optimized
growth. Both pathogens, H. influenzae and
V. cholerae offer excellent model systems to
study host/pathogen interaction, since both
cause significant diseases in humans
(meningitis and cholera), and already
established animal models are available to
investigate pathogenicity. For example,
during the past two years we unravelled the
molecular details of uptake and re-synthesis
pathway of the cofactor NAD in H. influenzae,
which as we showed is of critical importance
for the outcome of infection in the animal
model. There, we could also identify the key
proteins, resembling a novel system of a
coupled NAD-substrate uptake and resynthesis pathway. For H. influenzae other
important pathways have been characterized as well in our laboratory, focusing on
components involved in central metabolism,
oxygen sensitivity and signal transduction
regulatory pathways. For V. cholerae, we were
focusing on the role and functions of outer
membrane structures, such as porins, O
antigens, capsule, and core-oligosaccharides lipid A, all of which play a crucial
role in the establishment of initial colonization. Furthermore, we characterize the
molecular mechanism of the O antigen
attachment, which is con-served and of high
relevance for most of the Gram-negative
pathogens. In particular, we were unravelling
some biochemical pro-perties of the enzyme
O antigen ligase, which is the key component for O antigen attachment, and which
may become a subject for inhibitor development, targeting Gram-negative and LPS
producing bacteria.
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
Developmental biology of the fox-tapeworm
Echinococcus multilocularis and molecular
host-parasite interactions in alveolar
echinococcosis (Klaus Brehm)
Parasitic helminths infect more than 2
billion people world-wide. They are considered promising therapeutics against
autoimmune-diseases and allergies, and,
from the view of developmental biology, they
display several highly interesting traits.
Despite all this, parasitic helminths are a
neglected group of organisms when
compared to other infectious agents such
as bacteria, protozoa or fungi. Their cell
biological peculiarities are only rudimentarily
investigated and little is known concerning
the molecular basis of the complex hosthelminth interactions during an infection.
We are using one of these organisms, the
fox-tapeworm Echinococcus multilocularis,
as a model system to address fundamental questions regarding organ-tropism and
host-induced parasite development in
helminthic infections. On the one hand, we
approach a closer genetic characterization
of the parasite by means of several ESTand whole genome sequencing projects,
which also addresses basic questions
concerning the worm-specific processing
mechanism of mRNA trans-splicing. By
molecular genetic and biochemical approaches, we could show that E. multilocularis employs several signal transduction systems (insulin-, EGF, FGF-, TGFb-signalling) which are closely related to the
respective signalling systems of vertebrates
both on the structural and the functional level.
The most important tools of our investigations are several in vitro cultivation
systems which mimic the in vivo infection
situation and by which the development of
the parasitic larvae within the liver of host
organisms can be investigated under
laboratory conditions. Using these cultivation systems, we already showed that
soluble cytokines and hormones which are
present in the host liver during an infection
(e.g. insulin, EGF, BMP2) do have crucial
effects on the development and differentiation of parasitic larvae. Recently, we
demonstrated that the effect of these host
hormones on the parasite is mediated by
the evolutionary conserved signalling
systems that are shared between both
ZINFbericht-final.P65
43
organisms. In particular, we showed that
three host-derived hormones, insulin, EGF,
and BMP2, directly interact with corresponding surface receptors of the parasite
(host insulin binds to the insulin-receptorlike Echinococcus tyrosine kinase EmIR;
BMP2 functionally interacts with the TGFb-receptor-like kinase EmTR1) and stimulate corresponding intracellular signalling
cascades in E. multilocularis (host EGF
activates the parasite’s MAP kinase
cascade). These data indicate that parasitic helminths, contrasting to bacteria,
protozoa or fungi, utilize their phylogenetic
relationship with vertebrates to persist
within the host. Based on primary cell
cultivation systems for Echinococcus which
we have recently developed, promising
approaches to genetically manipulate the
parasite are currently under way, which will
be important for future studies concerning
the molecular basis of host-helminth
interactions.
43
Marianne Abele-Horn
27. November 1947
Academic career:
1969 – 1973 Studies of Pharmacy, Universities of Erlangen and Tübingen
1973 – 1979 Studies of Medicine, University of Freiburg and Medical School
Hannover
1977
PhD thesis in Pharmacy, Institute of Pharmacology,
University of Freiburg
1980 – 1993 Resident, Institute of Microbiology, Krankenhaus MünchenSchwabing
1984 – 1986 Resident, Department of Internal Medicine, Klinikum Rechts der
Isar, München
1994 – 1998 Consultant, Max von Pettenkofer-Institute, University München
since 1999 Consultant, Institute of Hygiene and Microbiology,
University Würzburg
2000
Habilitation in Medical Microbiology, University Würzburg
2005
Infectious Disease Specialist (DGI)
Selected Awards:
1993
Research Award (Deutsche Gesellschaft für Pädiatrische Infektiologie)
2000
Lectureship Award (International Organization for Mycoplasmology)
2000
Research Award (Deutsche Gesellschaft für Pädiatrische Infektiologie)
Editoral Work:
1998 – 2000 Co-editor „Infection“
Scientific Co-workers:
Dr. med. Dennis Tappe
Dr. med. Giuseppe Valenza
Prof. Dr. med. Dr. rer. nat.
Marianne Abele-Horn
Institut für Hygiene und Mikrobiologie
Josef-Schneider-Straße 2
97080 Würzburg
Phone ++49 931 201 46941
Fax ++49 (0)931 201-46445
[email protected]
23.04.2007, 14:49
44
3. Die Institutionen des Zentrums für Infektionsforschung
1990-1999
Christoph Schoen
15. Februar 1970
Dr. rer. nat.
Dr. med. Christoph U. Schoen
Institut für Hygiene und Mikrobiologie
University of Würzburg
Josef-Schneider-Str. 2
97080 Würzburg
Tel.: +49 931 201 46901
Fax:+49 931 201 46445
[email protected]
Studies of Physics and Medicine at the Ludwig-Maximilian-University,
Munich,and Georg-August-University, Göttingen
1999-2001 Medical Assistant (AiP) at the Clinic for General and Vascular Surgery,
Klinikum Bremen Mitte, and at the Clinic for Internal Medicine II, University
Hospital Würzburg
2000
M.D. thesis in Molecular Medical Mycology (Prof. R. Rüchel), Institute for
Medical Microbiology, Georg-August-University, Göttingen
2004
PhD in Microbiology (Prof. W. Goebel), Department of Microbiology,
Julius-Maximilians-University, Würzburg
2002-2003 Postgraduate degree in Bioinformatics, Ruprecht-Karls-University,
Heidelberg
2004Postdoc with Prof. Dr. M. Frosch, Institute of Hygiene and Microbiology,
University of Würzburg
2006Junior group leader
Fellowships/Awards:
1991-1996 Student fellowship of the Friedrich-Naumann-Stiftung
2000-2004 MD/PhD stipend of the BMBF
Senior Scientist:
Dr. Biju Joseph
Heike Claus
24.Juni 1961
Dr. rer. nat. Heike Claus
Institut für Hygiene und Mikrobiologie
Josef-Schneider-Str. 2
97080 Würzburg
Tel.: +49 931 201 46036
Academic career:
1989-1995 Studies of Biochemistry at the University of Hannover
1995-2000 PhD thesis at the Medical School Hannover and the
University of Würzburg
since 2000 Research Fellow at the Institute for Hygiene and Microbiology,
University of Würzburg
Fax: +49 931 201 46445
[email protected]
ZINFbericht-final.P65
44
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
Studies of Medicine at the Medical School Hannover
AiP at the Institute for Medical Microbiology, University of Mainz
Research Fellow at the Institute for Hygiene and Microbiology,
University of Würzburg
since 2002 Group leader at the Institute for Hygiene and Microbiology, University of
Würzburg
2006
Specialist for Microbiology, Virology and Infection Epidemiology
(Bayerische Landesärztekammer)
Research Topics:
Molecular basis of host-pathogen interaction in meningococcal meningitis
Project Management:
2003-2005 Interaction of Neisseria meningitidis with cells of the human blood brain
barrier Schwerpunktprogramm SPP1130 „Infektionen des Endothels“
since 2004 Interaction von Meningokokken und Gruppe B-Streptokokken mit
kardiovaskulären Zellen: Molekulare Mechanismen und pathophysiologische Bedeutung (IZKF University of Würzburg, A33)
45
1989-1996
1997-1998
1999-2002
Alexandra
Schubert-Unkmeir
12. November 1969
Dr.med. Alexandra Schubert-Unkmeir
Institut für Hygiene und Mikrobiologie
University of Würzburg
Josef-Schneider-Str. 2
97080 Würzburg
Tel.: +49 931 201 46901
Fax: +49 931 201 46445
[email protected]
1994-2001
2002
200220062007-
study in medicine, University of Würzburg
MD thesis in Medical Microbiology (Prof. M. Frosch), Institute of Hygiene &
Medical Microbiology, Würzburg
Post-Doc, Institute of Hygiene & Medical Microbiology, Würzburg
Group leader IZKF A50 „Interaction of pathogenic fungi with human
neutrophils“
Group leader SFB 479 „In vivo relevant expression of virulence genes of
N. meningitidis“
Awards:
1994-2001 Student Fellowship of the Studienstiftung des Deutschen Volkes
2002
DGHM Becton-Dickinson Dissertation Award
2003
Dissertation Award of the Medical Faculty Würzburg
2003
Science Award of the Unterfränkische Gedenkjahrstiftung
2005
Travel Grant (Instand e.V.)
Senior Scientist:
Dr. Corinna Schmitt
ZINFbericht-final.P65
45
23.04.2007, 14:49
Oliver Kurzai
23. August 1975
Dr. med. Oliver Kurzai
IInstitut für Hygiene und Mikrobiologie
Josef-Schneider-Strasse 2
97080 Würzburg.
Tel.: +49 931 201 46905
Fax: +49 931 201 46445
[email protected]
46
3. Die Institutionen des Zentrums für Infektionsforschung
3.4 Lehrstuhl für Mikrobiologie
Theodor-Boveri-Institut,
Biozentrum
Der Lehrstuhl für Mikrobiologie hat eine
lange Tradition in der Charakterisierung
der molekularen Grundlagen der Wechselwirkung zwischen Bakterien und ihren
eukaryontischen Wirten. Der Schwerpunkt
liegt dabei auf humanpathogenen Keimen, wobei verschiedene Modellorganismen untersucht werden. Als Bespiel für
fakultativ intrazelluläre Erreger werden in
den Arbeitsgruppen von Werner Goebel
und Jürgen Kreft Listerien benutzt. Listeria
monocytogenes kann durch kontaminierte
Nahrungsmittel aufgenommen werden
und in immunsupprimierten Patienten
schwere Krankheitsbilder mit einer hohen
Mortalitätsrate verursachen, wie z.B.
Sepsis oder Hirnhautentzündung. Eine
besondere Eigenschaft dieses Erregers
ist zudem, dass er intrauterin von der
Mutter auf den Fötus übertragen werden
kann, was zum Abort oder zu einer besonders schweren Erkrankung (Granulomatosis infantiseptica) des neugebo-
Werner Goebel
19. September 1939
Academic Curriculum:
1963-63
Studies of Chemistry at the University of Tübingen
1965-65
PhD Thesis (supervisor Prof. Dr. F. Lingens)
1966-69
Research Fellow with Prof. Helinski, University of California
San Diego/ La Jolla
1969-71
Research Assistant at the Institute for Microbiologiy University of
Hohenheim (Prof. Lingens)
1971
Habilitation in Microbiology and Biochemistry at the University of
Hohenheim
1972-75
Head of the Genetics Department at the GBF in Stöckheim,
concomitantly H3-Professor for Biochemistry at the University of
Braunschweig
since 1975 Chair of Microbiology at the University of Würzburg
Selected Functions and Awards:
1983
Robert-Koch Award
1984
ASM Lecture Award
2006
Emil-von-Behring Award
Member of several academies such as the Leopoldina and the American
Academy for Microbiology
Prof. Dr. Werner Goebel
Lehrstuhl für Mikrobiologie
Biozentrum der Universität Würzburg
Am Hubland
97074 Würzburg
Germany
Tel: +49 (0)931 - 888 - 4400
Fax: +49 (0)931 - 888 - 4402
[email protected]
ZINFbericht-final.P65
46
renen Kindes führt. Die Arbeiten beinhalten folgende Schwerpunkte: (a) Einblicke in die Evolution von Virulenzeigenschaften, die einige harmlose
Umweltbakterien dieses Genus wie L.
seeligeri oder L. innocua vom pathogenen
Keim L. monocytogenes unterscheiden;
(b) das Verständnis der bakteriellen
Faktoren, die am Virulenzgeschehen
beteiligt sind, und die Regulation der
Expression dieser Faktoren; (c) die
metabolischen Voraussetzungen von L.
monocytogenes, die es diesem Bakterium
ermöglichen sich nach seinem Vordringen in das Cytosol der eukaryontischen Zell dort zu vermehren; d) Reaktionen der Wirtszelle nach Invasion durch
die Bakterien. Bei diesen Untersuchungen spielen moderne genomische
Techniken wie Transkriptom- und Proteomcharakterisierungen eine besondere
Rolle, da mittlerweile die Genomsequenzen mehrerer Listeria Arten (L.
innocua, L. ivanovii, L. seeligeri und L. welshimeri), sowie verschiedener Serotypen
von L. monocytogenes vorliegen.
Viele der in diesen Projekten erhaltenen
Erkenntnisse werden in der Arbeitsgruppe
von Werner Goebel dazu benutzt, neuartige Lebendimpfstoffe gegen verschiedene Krankheitserreger bzw. therapeutische Impfstoffe gegen bestimmte Krebserkrankungen zu entwickeln. Der Ansatzpunkt dieser Untersuchungen liegt
darin begründet, dass L. monocytogenes
in das Cytosol einer eukaryontischen Zelle
vordringen kann. Es wurden apathogene
Varianten dieser Bakterien erzeugt, die
zwar noch in das Cytosol vordringen, sich
dort aber nicht mehr vermehren können.
Diese Bakterien kodieren für ein Enzym,
das die Lyse der Bakterien verursacht,
sobald sie sich im Cytosols der Wirtszelle
befinden. Enthalten die Bakterien z.B.
einen DNA-Impfstoff, wird dieser durch die
Lyse der Bakterien im Cytosol freigesetzt
und kann dort im günstigen Fall die
gewünschte Immunreaktion auslösen.
Weitere fakultativ intrazelluläre Erreger, die
am Lehrstuhl bearbeitet werden, sind
verschiedene pathogene Enterobakterien
wie Salmonellen und enteroinvasive E.
coli (EIEC) Stämme. Auch in diesen
Projekten stehen ähnlich wie bei den
oben genannten Listerien Fragen zur
Aufnahme der Bakterien in ihre eukaryontischen Wirtszellen und ihrer Fähigkeit, sich in diesen Zellen zu vermehren,
im Mittelpunkt.
Als Modellorganismen für extrazelluläre
Erreger werden am Lehrstuhl Bakterien
der Gattungen Helicobacter und Bordetella
untersucht. Helicobacter pylori hat sich auf
den menschlichen Magen als Habitat
spezialisiert und verursacht verschiedene
Erkrankungen, darunter Magengeschwüre. Eine lange anhaltende Infektion mit
diesem Erreger kann aber auch zu
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
Magenkrebs oder zum MALT-(mucosaassoziiertes Lymphgewebe)-Lymphom
führen. In der Arbeitsgruppe von Dagmar
Beier werden schwerpunktmäßig Fragen
der Wahrnehmung von Umweltreizen und
der daran gekoppelten Regulation genetischer Programme in H. pylori und eng
verwandten Bakterien, sowie die Regulation der bakteriellen Chemotaxis untersucht. Der Genus Bordetella beinhaltet
eine Reihe human- oder tierpathogener
Arten. In der Arbeitsgruppe von Roy Gross
werden die molekularen Mechanismen
der Evolution von Virulenzeigenschaften
in diesem Genus untersucht, die ausgehend von Umweltorganismen wie B.
petrii zur Entstehung des Keuchhustenerregers B. pertussis geführt haben.
Da mittlerweile auch für dieses Genus die
genomischen Sequenzen einer ganzen
Reihe von Arten ermittelt wurden, kommen
auch hier moderne genomische Methoden
zum Einsatz. Einen zweiten Schwerpunkt
bilden, wie auch bei der Charakterisierung
von Helicobacter, Untersuchungen zur
Wahrnehmung von Umweltreizen durch
diese Bakterien, die dadurch die Expression ihrer Virulenzgene umweltbedingt regulieren können.
Im Gegensatz zu den vorher genannten
Projekten wird in der Arbeitsguppe von Roy
Gross eine symbiontische Beziehung von
obligat intrazellulären Bakterien des
Genus Blochmannia mit ihren Wirtstieren,
Ameisen der Gattung Camponotus, untersucht. Die kürzlich fertiggestellte Genomsequenz von Blochmannia floridanus
zeigt auf, dass diese Bakterien eng mit
pathogenen Enterobakterien verwandt
sind, dass sie eines der kleinsten bisher
bekannten Genome haben und lässt
zudem vermuten, dass sie ihren Wirtstieren bestimmte Nährstoffe wie z.B.
essentielle Aminosäuren zuführen.
In der Arbeitsgruppe von Aladar Szalay
wird der Einsatz von attenuierten pathogenen Mikroorganismen als Lebendimpfstoffe untersucht. Die Beobachtung,
dass intravenös applizierte Bakterien,
Vaccinia Virus und Säugerzellen, in solide
Tumoren und Metastasen eindringen,
replizieren und persistieren, öffnet neue
Wege für Mikroben-basierte kombinierte
Tumordiagnostik und Therapie. Zusätzlich
zu Schwachlicht (Lumineszenz) Emmission durch genetisch veränderte
Luziferase Gene tragen die Lebendvektoren Gene zur simultanen Detektion
und Therapie von Tumoren in lebenden
ZINFbericht-final.P65
47
47
Versuchstieren. Während der Kolonisierung der Tumoren, die im Rückgang
und der Eliminierung des Tumors führt,
wird die Konzentration an Zytokinen,
Chemokinen und Wachstumsfaktoren
parallel zur Rekrutierung und Aktivierung
von Immunzellen gemessen. Dabei werden RT-PCR, Mikroarrays und immunohistochemische Methoden eingesetzt. Die
Arbeitsgruppe erwartet, den Beitrag von
humanen Tumorzellen und von Mausstroma bestimmen zu können, der die
bakteriolytische und onkolytische Eliminierung der soliden Tumoren und
Metastasen durch das wirtseigene (autologe) Immunsystem ermöglicht.
Eliminierung der soliden Tumoren und
Metastasen durch das wirtseigene (autologe) Immunsystem ermöglicht.
3.4 Chair of Microbiology,
Theodor-Boveri-Institute,
Biocenter
The Chair of Microbiology has a long
tradition in the characterization of the
molecular basis of the interaction of
bacteria and their eukaryotic hosts. The
main emphasis lies on those bacteria that
are pathogens for man. As an example of
facultatively intracellular agents, in the
groups of Werner Goebel and Jürgen Kreft,
bacteria of the genus Listeria are investigated. Listeria monocytogenes can be
transmitted by contaminated food and can
cause severe diseases in immunocompromised patients such as meningitis and
septicemia. A feature of high relevance is
the fact that the agent can be transmitted
intrauterine from the mother to the fetus
which may cause either abortion or a
severe systemic disease (granulomatosis infantiseptica) in the newborn. The
project is focused on the following points:
(a) insights in the evolution of the pathogenic properties, which distinguishes
harmless environmental species such as
L. seeligeri and L. innocua from the
pathogenic species L. monocytogenes; (b)
the characterization of the bacterial factors
relevant for virulence and the regulation of
expression of these virulence factors; (c)
the metabolic prerequisites of L. monocytogenes which enable this bac-terium
to multiply within the cytosolic compartment of eukaryotic cells; d) reactions
of the host cell on invasion by these
23.04.2007, 14:49
Selected References:
- Eisenreich, W., Slaghuis, J., Lauptiz,
R., Bussemer, J., Stritzker, J., Schwarz,
C., Schwarz, R., Dandekar, T.,
Goebel , W. and Bacher, A. (2006)
13C isotopolouge perturbation studies
of Listeria monocytogenes carbon
metabolism and its modulation by the
virulence regulator PrfA. Proc Natl Acad
Sci USA 103: 21040-2045.
- Joseph, B., Przybilla, K., Stuhler, C.,
Schauer, K., Slaghuis ,J., Fuchs, T.M.
and Goebel, W. (2006) Identifcation of
Listeria monocytgenes genes contributing to intracellular regplation by
expression profiling and mutant screening. J Bacteriol 188: 556-568.
- Schoen, C., Kolb-Mäurer, A., Geginat,
G., Löffler, D., Bergmann, B., Stritzker,
J., Szalay, A.A., Pilgrim, S. and
Goebel, W. (2005) Bacterial delivery
of functional messenger RNA to
mammalian cells. Cell Microbiol 7: 709724.
48
3. Die Institutionen des Zentrums für Infektionsforschung
Fig. 1:
Listeria monocytogenes as vehicle for
DNA vaccines. The genetic information
coding for a relevant antigen is transported via bactofection into an antigen
presenting cell (1) und is liberated in
the cytosol (2). Production of the antigen
by the host cell (3) and presentation on
the cell surface (4), thus triggering an
immune response against the antigen.
bacteria, which can reach the cytosol of
the host cell where they multiply. Important
tools for these studies are modern genome based technologies such as the
characterization of the transcriptome and
proteome of these bacteria, since in the
meantime the genomic sequences of
several Listeria species (L. innocua, L.
ivanovii, L. seeligeri, and L. welshimeri)
and even of several serotypes of L.
monocytogenes are available.
Several of the insights gained by these
projects are used by the group of Werner
Goebel to develop novel types of live
vaccines against various pathogens or
therapeutic vaccines against certain types
Selected references:
-Dominguez-Bernal, G., Müller-Altrock,
S., Gonzalez-Zorn, B., et al. (2006) A
spontaneous genomic deletion in
Listeria ivanovii identifies LIPI-2, a
species-specific pathogenicity island
encoding sphingomyelinase and numerous internalins. Mol Microbiol
59:415-432.
- Gopal, S., Borovok, I., Ofer, A., Yanku,
M., Cohen, G., Goebel, W., Kreft, J.,
and Aharonowitz, Y. (2005) A multidomain fusion protein in Listeria
monocytogenes catalyzes the two
primary activities for glutathione
biosynthesis. J Bacteriol 187:38393847.
- Hain, T., Steinweg, C., Kuenne, C.T.,
Billion, A., et al. (2006) Whole-genome
sequence of Listeria welshimeri reveals
common steps in genome reduction
with Listeria innocua as compared to
Listeria monocytogenes. J Bacteriol
188:7405-7415.
of cancer. The basis of these investigations is the fact that L. monoytogenes
is able to reach the cytoplasm of its host
cell. Variants of L. monocytogenes have
been constructed which are not anymore
pathogenic. These variants still are able
to reach the cytoplasm of the host cell, but
they have lost their ability to multiply
therein. The bacteria code for an enzyme
which causes the lysis of the bacteria
upon their entrance in the cytosol of the
host cell. If such bacteria contain a DNAvaccine it will be released into the cytosol
and may therefore cause the desired
immune response.
Additional facultative intracellular pathogens worked with at the Chair of Microbiology comprise various Enterobacteriaceae among which there are Salmonella and enteroinvasive E. coli (EIEC)
strains. In these projects similar questions
are delt with as in the case of the Listeriae
such as the invasion strategies of these
bacteria and their ability to multiply within
the eukaryotic host cell.
ZINFbericht-final.P65
48
As model organisms for extracellular
pathogens, bacteria of the genera Helicobacter and Bordetella are investigated.
Helicobacter pylori has specialized to the
human stomach as its unique habitat and
can cause different kinds of disease such
as ulcers. Long lasting infections with
these bacteria can also generate stomach
cancer or the MALT (mucosa associated
lympoid tisse) lymphoma. In the group of
Dagmar Beier the molecular basis of the
perception of environmental signals such
as acid and the changes in the genetic
programs of H. pylori and closely related
bacteria as a response of changes in
these signals are investigated. Moreover,
the regulation of the chemotactic response
of H. pylori is analysed. The genus
Bordetella comprises a series of human
or animal pathogens. In the group of Roy
Gross the molecular mechanisms leading
to the evolution of virulence properties in
these bacteria are investigated, which led
from environmental organisms such as
Bordetella petrii to the emergence of B.
pertussis, the etiological agent of whooping cough. Since several genomic
sequences of various Bordetella species
are available since recently, modern
genomic techniques are applied for these
investigations. The second project involves the characterization of signal
transduction systems of the various
Bordetella species, which are involved in
the coordinated regulation of virulence
gene expression according to changing
environmental conditions.
Contrary to all previous projects, in the
group of Roy Gross a mutualistic relationship between obligate intracellular
bacteria of the genus Blochmannia and
their animal hosts, ants of the genus
Camponotus, is investigated. The genome sequence of Blochmannia floridanus was recently established and
revealed that this bacterium is closely
related to pathogenic Enterobacteriaceae,
that it has one of the smallest genomes
so far described, and that the bacteria very
likely supply the host organism with certain
nutrients such as essential amino acids.
In the group of Aladar Szalay the use of
attenuated pathogens as live vectors is
investigated. The discovery that intravenously injected bacteria, Vaccinia virus
and mammalian cells, enter, replicate and
persist in solid tumours and metastases
opens the way for microorganism based
combined tumour diagnostics and therapy. In addition to low light (luminescence)
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
emission by engineered luciferase genes,
the live vectors do carry different therapeutic genes for simultaneous detection
and therapy of tumours in live animal
models. During tumour colonization,
which results in tumor regression and
elimination, the presence of cytokines,
chemokines and growth factors is monitored in parallel with the recruitment and
activation of immune cells using RT PCR,
microarrays and immuno-histochemical
methods. The group expects to dissect the
contribution of the human tumour cells and
that of the mouse stroma to bacteriolytic
and oncolytic elimination of solid tumours
and metastases by the host (autologous)
immune system.
3.4.1 Post-genomic analysis of Listeria
virulence (Jürgen Kreft)
Listeriae are ubiquitous, very robust grampositive bacteria. The two species L.
monocytogenes and L. ivanovii can cause,
in humans and animals, the rare but often
fatal disease listeriosis. From their natural
habitat (decaying plant matter in soil) the
bacteria easily contaminate food and thus
can reach their eukaryotic hosts. There
they cross the intestinal barrier, multiply
with in the spleen and liver and eventually
may even breach the blood-brain and
placentar barrier, causing e.g. meningoencephalitis or a severe systemic infection
of the unborn. L. monocytogenes has
evolved very sophisticated mechanisms
to invade its primary eukaryotic host cells,
to multiply therein and to spread to other
cells. It is regarded as a model organism
for the important group of facultative
intracellular bacterial pathogens, which
includes e.g. the causative agent of
tuberculosis. In 2001, with a significant
contribution from the Würzburg Listeria
research group, the complete genome
sequences of one isolate of L. monocytogenes and its close, but harmless
relative L. innocua, have been published.
Further Listeria genomes have been
completed by the Würzburg-based PathoGenoMik competence network. The genome sequence of the environmental
species L. welshimeri has been published
recently. This opened an avenue for the
identification of novel virulence factors,
using first comparative genome analysis
and then precisely targeted genetic and
biochemical experiments.
ZINFbericht-final.P65
49
Using this combined approach, the working group focuses on the following
aspects:
- Low molecular weight protein-tyrosine
phosphatases (LMW-PTPs). For other
pathogens it has been shown that such
enzymes are involved in the regulation of
virulence. Infection experiments with L.
monocytogenes mutants deleted for LMWPTP genes showed a defect in invasiveness. In transcription studies, using whole
genome microarrays, we could identify
several candidate genes responsible for
these biological effects. Gene-specific
analyses using quantitative reversetranscription PCR („real time RT-PCR“)
corroborated a pleiotropic effect of the
49
Jürgen Kreft
27. September 1945
Scientific Career:
1967-1969 Studies of Biology at the TH Stuttgart
1970-1972 Studies of Biology at the University of Hohenheim
1977 PhD Thesis at the University of Stuttgart
1977 Research Fellow and Group leader at the Chair of Microbiology,
University of Würzburg
1984 Habilitation in Microbiology at the University of Würzburg
1992 Appointment for Professorship at the Chair of Microbiology,
University of Würzburg
Fellowships and Awards:
1987 Deputy Chairman of the Diploma Committee for Biology
1998 Award of the „Seeliger-Stiftung“
2005 Gay-Lussac/Humboldt Award
Listeria LMW-PTPs on the transcription
and also the translation of numerous
genes. Among them are genes for invasion
factors of the internalin family, an important
motility gene and genes for stress proteins. The influence of the phosphatases
on the multiplication and the metabolism
of Listeria will be investigated further, as
well as the biochemical characteristics of
these enzymes.
Prof. Dr. rer. nat. Jürgen Kreft
Biozentrum Lehrstuhl für Mikrobiologie
Am Hubland
97074 Würzburg
Tel.: +49 (0)931 888 4419
Fax: +49 (0)931 888 4402
[email protected]
Fig.2: Scanning electron micrograph of Listeria invading
Caco-2 enterocytes
23.04.2007, 14:49
50
3. Die Institutionen des Zentrums für Infektionsforschung
- Glutathione synthetase. Glutathione
(gamma-glutamyl-cysteine-glycine, GSH)
is an important, redox-active thiol in many
cells. The original annotation of the L.
monocytogenes genome classified the
GSH biosynthetic pathway as being
incomplete, missing the gene for the
second enzyme, glutathione synthetase
(GshB). In a collaboration with the Tel Aviv
University (Prof. Y. Aharonowitz) we could
characterize a novel bifunctional enzyme,
GshF, which combines all the necessary
catalytic activities in one polypeptide. Such
an unusual enzyme seems to be present
also in other bacteria. We have generated
mutations in other genes of the so called
thiol-redox metabolic network (TRMN) of
L. monocytogenes. The comprehensive
genetic, biochemical and functional
analysis of the TRMN, performed together
with the Israeli partner, will be the focus of
our future research.
Roy Gross
11. Oktober 1956
Scientific career:
1976-1981
Studies of Biology at the Eberhard-Karls-University of Tübingen
1981-1982
Diploma Thesis under the Supervision of Prof. Dr. V. Braun
1982
Diploma (Master of Science)
1982-1985
PhD Thesis under Supervision of Prof. Dr. V. Braun
1985-1989
Postdoctoral Research Fellow at the Sclavo
Research Center in Siena, Italy
1990-1991
Research Scientist at the Pasteur Institut, Paris, with Prof. Dr. A.
Ullmann
1991
Research Assistant (C1) at the Chair of Microbiology, University of
Würzburg with Prof. Dr. W. Goebel
1993
Qualified as University Lecturer in Microbiology (Habilitation)
1994
Assistant Professor at the Chair of Microbiology, University of
Würzburg
1997
Appointment as an Associate Professor for Microbiology (C3) at the
University of Würzburg
Fellowships and awards
Various fellowships from the European Union, EMBO, HFSPO
1990
Young Investigator Award of the DGHM
since 2004
Member of the Editorial Board of the Journal „Microbes and Infection“
since 2006
Member of the Editorial Board of the Journal „BioSpektrum“
3.4.2 Virulence properties and their
evolution in the genus Bordetella (Roy
Gross)
Prof. Dr. rer. nat. Roy Gross
Biozentrum Lehrstuhl für Mikrobiologie
Am Hubland
97074 Würzburg
Tel.: +49 (0)931- 888 -4403
Fax: +49 (0)931- 888 -4402
[email protected]
ZINFbericht-final.P65
50
The genus Bordetella consists of several
highly related pathogenic species including the etiological agent of whooping
cough, B. pertussis, and several animal
pathogens such as B. bronchiseptica.
These bacteria produce many virulence
related factors, among which there are
several adhesins such as the filamentous
hemagglutinin (FHA), the per-tactin (PRN)
and the fimbriae, and several toxins such
as the adenylate cyclase toxin (CYA) and
the pertussis toxin (PTX) that is exceptionally produced only by B. pertussis. The
expression of these factors is regulated
according to environmental stimuli such
as temperature. The two-component
system BvgAS is required for this environmental regulation of virulence factors and
consists of the transmembrane histidine
kinase BvgS and the cytoplasmic transcription factor BvgA. BvgS is the sensor
protein that transforms the environmental
stimuli into a cellular signal via several
phosphorylation events, which finally lead
to activation of BvgA. The BvgA protein then
interacts with the promoters of the virulence genes and induces their transcription.
A major research interest regards the molecular characterization of the regulatory
mechanisms which control virulence gene
expression. The BvgAS system belongs
to a small subfamily of unorthodox twocomponent systems, which are characterized by a more complex domain structure than the classical systems. In contrast
to classical sensor proteins the BvgS
protein contains additional C-terminal
signalling domains. A complex multistep
phosphorelay between alternating histidine and aspartate residues occurs in
those unorthodox systems. Mutation and
complementation analyses demonstrated
that in contrast to other unorthodox sensor
proteins these additional domains are
essential for BvgS function indicating that
the phosphorelay is obligate in this
system. By the comparison of the structurally related BvgAS and EvgAS (from E.
coli) two-component systems we could
demonstrate the importance of the Cterminal domains of the unorthodox
sensor proteins for the specificity of the
signal transduction process and the
activation of the BvgA and EvgA effector
proteins. By a detailed structure-function
analysis based on a combination of
biophysical, biochemical and genetic
approaches, we could demonstrate that
the transcription factors BvgA and EvgA are
dimers even in the non phosphorylated
form. Moreover, our investigations have
provided evidence that the BvgS and EvgS
histidine kinases are responsive to the
oxidation status of the electron carrier
ubiquinone (Q-8) in addition to the previously known environmental signals such
as temperature. This indicates that the
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
virulence regulon of the pathogenic
Bordetellae is linked with the energy state
of the bacteria.
The second focus of this project regards
evolutionary processes which led to the
expression of different pathogenic properties in the various Bordetella species.
We compare the classical Bordetella
species B. pertussis, B. parapertussis and
B. bronchiseptica with new Bordetella
species which have been isolated from
patients only recently such as B. holmesii,
B. hinzii and B. trematum. Of special
interest is a new organism, B. petrii,
isolated from a river sediment, which is
an environmental isolate most closely
related to members of the genus Bordetella. The project involves the comparison of species specific putative
virulence properties such as invasion
mechanisms in epithelial cells, intracellular survival in professional phagocytes, resistance mechanisms against
stress inducing agents and host specific
antimicrobial compounds (e.g. defensins). In addition, we identify and characterize genetic differences between the
different species which provide insights
in the molecular mechanisms of evolution
within this group of important pathogens.
Recently, we have determined the genomic sequence of the environmental
organism B. petrii. The comparison of this
sequence with those of the mammalian
pathogens allow us to get insights in the
evolution of virulence properties in the
genus Bordetella. First results indicate that
all species including the environmental
isolate B. petrii code for orthologous
genes encoding the BvgAS system,
fimbriae, FHA and other putative virulence
factors.
3.4.3 Intracellular bacterial endosymbionts
of insects (Roy Gross)
More than a 100 years ago F. Blochmann
described the presence of intracellular
bacteria in midgut and ovarial cells of ants
of the genus Camponotus. Recently we
started to investigate this symbiotic
relationship on the molecular level.
Cloning and analysis of the 16S rRNA
genes of the symbiotic bacteria of fourteen
Camponotus species collected in Europe
and Southern- and Northern America
allowed their classification within the
gamma-subclass of the Proteobacteria.
The ant symbionts are more closely
related to each other than to any other
known organism and have recently been
proposed to be members of a novel
genus: Candidatus Blochmannia (gen.
nov.). The closest relatives are endosymbiotic bacteria of the tsetse fly (Wigglesworthia spp.) and of aphids (Buchnera
aphidicola) which together form a huge
cluster of symbiotic organisms and have
a common ancestor with the Enterobacteriaceae. In parallel to the phylogenetic analysis of the bacteria we performed a related analysis with the host
animals characterizing their mitochondrial
cytochome oxidase subunit I gene sequences. Interestingly, the phylogenetic
trees of the ants and their symbionts are
congruent indicating a long lasting cospeciation of these organisms. In fact, the
bacteria appear to be transmitted maternally, as in situ hybridization with sym-
Fig. 3: Porposed metabolic interactions
of Blochmannia floridanus and its host
Camponotus floridanus deduced from
the genome of B. floridanus
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23.04.2007, 14:49
51
Selected References:
-Beier, D., and Gross, R. (2006)
Regulation of bacterial virulence by
two-component systems. Curr Opin
Microbiol 9: 1-10.
-Stübs, D., Fuchs, T.M., Schneider, B.,
Bosserhoff, A., and Gross, R. (2005)
Identification and regulation of cold
inducible factors of Bordetella bronchiseptica. Microbiology 151: 18951909.
-Zientz, E., Beyaert, I., Gross, R. and
Feldhaar, H. (2006) Relevance of the
endosymbiosis of Blochmannia floridanus and carpenter ants at different
stages of the life cycle of the host. Appl
Env Microbiol 72: 6027-6033.
52
3. Die Institutionen des Zentrums für Infektionsforschung
biont specific oligonucleotides unequivocally showed the bacteria in the midgut
and in the ovaries to be identical. The
characterization of the symbiont migration
during embryogenesis by in situ hybridization revealed an early association of the
bacteria with endodermal tissues. The
genomic sequence of Blochmannia has
recently been determined. This sequence
confirms the close relationship of Blochmannia with the Enterobacteriaceae.
Similar to other bacteriocyte symbionts,
Blochmannia has a strongly reduced
genome size of about 705 kb. The aim of
this study is to investigate the molecular
basis of this symbiosis, adaptation
mechanisms of the partners to each other
and to understand the biological significance of this interspecies interaction.
3.4.4 Two-component signal transduction
in Helicobacter pylori (Dagmar Beier)
Helicobacter pylori colonizes the human
gastric mucosa and is the aetiologic agent
of chronic gastritis and peptic ulcer disease.
In addition, infection with H. pylori is a risk
factor for the development of gastric
malignancies like adenocar-cinoma and
MALT lymphoma. Probably as a consequence of its tight adaptation to the human stomach as its exclusive niche H.
pylori contains only a very restricted
repertoire of transcriptional regulators. The
genome of H. pylori encodes three histidine kinases and five response regulators belonging to the family of twocomponent signal transduction system
Dagmar Beier
31. März 1964
which are involved in transcriptional
regulation. Interestingly, the few twocomponent proteins of H. pylori show
unexpected properties. Two of the five
response regulators are essential for cell
growth, while the three histidine kinase
genes can be deleted without effect on the
growth phenotype. In addition, the sequence of the N-terminal receiver domains of two-response regulators differs from
the consensus sequence at usually highly
conserved positions suggesting a mode
of activation of these regulator proteins
which differs from the well-known twocomponent paradigm. All two-component
proteins are required for colonization in a
mouse model of infection. In case of the
ArsRS two-component system this observation can be explained by the fact that
ArsRS in response to acidic pH regulates
the expression of genes involved in the
pronounced acid resistance of H. pylori.
The ArsRS-regulated genes include the
urease gene cluster encoding the major
acid-resistance determinant of H. pylori
which is essential for host colonization. The
aim of the project is the functional characterization of the two-component proteins
of H. pylori as well as the identification and
characterization of target genes which are
under control of the two-component
systems. Of particular interest are essential regulated genes which might be targets
for the development of new therapeutic
stratagies against H. pylori infections.
A complex two-component system participates also in chemotactic signalling.
Interestingly, the composition of the
Scientific career:
1983-1989 Studies of Chemistry at the University of Würzburg
1992 PhD thesis at the University of Würzburg
1992-1995 Postdoctoral fellow at the Chair of Microbiology, University of Würzburg
1995-1998 Postdoctoral fellow at the Immunobiological Research Institute Siena
(IRIS)
2002 Habilitation
PD Dr. rer. nat. Dagmar Beier
Biozentrum Lehrstuhl für Mikrobiologie
Positions, fellowships:
1998 group leader
1992-1995 Postdoctoral fellowship, Deutsche Forschungsgemeinschaft (DFG)
1995-2000 AIDS-fellowship, Federal Ministry of Education and Research
2000-2002 Research fellowship (Habilitations-Stipendium), DFG
Am Hubland
97074 Würzburg
Tel.: ++49 (0)931- 888-4421
Fax: ++49 (0)931- 888-4402
[email protected]
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3. Institutions of the Research Center for Infectious Diseases
Fig.4: Two-component systems of H. pylori involved in transcriptional regulation
chemotactic apparatus of H. pylori differs
markedly from the well-studied enterobacterial system and shows some similarity to the chemotactic system of Sinorhizobium meliloti. We are focussing on
the characterization of the complex phosphotransfer reactions between the different two-component proteins which
control chemotactic signalling in H. pylori.
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Selected references:
-Pflock, M., Finsterer, N., Joseph, B., Mollenkopf, H., Meyer, T.F., and Beier, D. (2006)
Characterization of the ArsRS regulon of
Helicobacter pylori involved in acid adaptation.
J Bacteriol 188: 3449-3462.
-Pflock, M., Kennard, S., Delany, I., Scarlato,
V., and Beier, D. (2005) Acid-induced activation
of the urease promoters is mediated directly
by the ArsRS two-component system of
Helicobacter pylori. Infect Immun 73: 6437-6445.
-Schär, J., Sickmann, A., and Beier, D. (2005)
Phosphorylation-independent activity of
atypical response regulators of Helicobacter
pylori. J Bacteriol 187: 3100-3109.
23.04.2007, 14:49
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54
3. Die Institutionen des Zentrums für Infektionsforschung
3.5 Institut für Molekulare
Infektionsbiologie
Das Institut für Molekulare Infektionsbiologie wurde im Jahre 1993 als interdisziplinäre Einrichtung an der Medizinischen
Fakultät der Universität Würzburg gegründet. Da der Lehrstuhlinhaber gleichzeitig
Mitglied der Medizinischen und Biologischen Fakultät ist, wurde das Institut schon
bei seiner Gründung mit dem Ziel angelegt, eine „Scharnierstelle“ zwischen den
beiden Fakultäten zu sein. Es bestehen
auch wissenschaftliche Beziehungen zu
den Fakultäten für Chemie und Pharmazie
und für Physik. Die am Institut bearbeiteten Projekte befassen sich mit molekularen Aspekten von Infektionsprozessen.
Weiterhin wird Infektionsbiologie in der
Lehre vertreten. Dabei werden LehrJörg Hinrich Hacker
veranstaltungen vor allem für Biologie- und
13. Februar 1952
für Biomedizinstudenten, aber auch für Studenten der Medizin und der Zahnmedizin
angeboten. Die Graduiertenausbildung
spielt eine große Rolle beim Lehrengagement der Mitglieder des Institutes, die sich
auch an der Etablierung der „Graduate
School of Life Sciences“ der Universität
Würzburg beteiligt haben.
Die Arbeitsgruppen des Instituts für Molekulare Infektionsbiologie befassen sich mit
den vielfältigen, molekularen Aspekten von
Infektionen, die durch Bakterien, Parasiten
und Pilzen hervorgerufen werden. In der
Arbeitsgruppe „Molekulare Parasitologie
und Infektionsimmunologie“ (Leiterin H.
Moll) werden insbesondere die Interaktionen zwischen parasitären Infektionserregern und dem Immunsystem analysiert. Die Arbeitsgruppe „Molekulare Mykologie“ (Leiter: J. Morschhäuser) befaßt sich
mit den Krankheitsprozessen bei Pilzinfektionen. Die bakteriologischen Arbeitsgruppen untersuchen ein breites Spektrum
Prof. Dr. Dr. h. c. mult. Jörg Hacker
an Erregern, wobei sowohl EnterobakInstitut für Molekulare Infektionsbiologie
terien, Gram-positive Bakterien wie StaphyRöntgenring 11
lokokken und Enterokokken als auch
97070 Würzburg
Legionellen in die Studien mit einbezogen
Tel.: ++49-931-312575
werden. Es werden sowohl die InteraktioFax: ++49-931-312578
nen zwischen den Erregern und den [email protected]
zellen als auch die dynamischen Prozeswww.infektionsforschung.unise der Erregervariabilität beleuchtet.
wuerzburg.de
Am Institut für Molekulare Infektionsbiologie
sind ca. 50 Personen tätig, neben Wissen(curriculum vitae of Jörg Hacker,
schaftlern, Doktoranden, Diplomanden,
see page 6)
ZINFbericht-final.P65
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auch Gastwissenschaftler aus dem In- und
Ausland. Die Arbeit wird vor allem über Drittmittel der Deutschen Forschungsgesellschaft (DFG), des Bundesministeriums
für Bildung und Forschung (BMBF), der Europäischen Union (EU) und anderer
Förderungsorganisationen finanziert. Mitarbeiter des Instituts für Molekulare
Infektionsbiologie sind in verantwortlichen
Positionen in den Selbstverwaltungsorganisationen der Universität, in Fachgesellschaften und forschungsfördernden Institutionen des In- und Auslandes tätig. Besonders intensive Beziehungen bestehen
zu den Nachwuchsgruppen des Zentrums
für Infektionsforschung, die organisatorisch mit dem Institut für Molekulare
Infektionsbiologie assoziiert sind und mit
dem ein enger Austausch auf wissenschaftlichen Gebiet erfolgt.
3.5 Institute for Molecular
Infection Biology
The Institute for Molecular Infection Biology
was founded in 1993 as an interdisciplinary institution at the Medical Faculty
of the University of Würzburg. As the
chairman has also been a member of the
Faculty of Biology, one of the first objectives
of the institute was to represent a link
between these two faculties. Furthermore,
an intensive scientific and organizational
relation has been build to the faculties of
pharmacy, chemistry and physics. The
research of the institute aims to elucidate
fundamental aspects of infection processes. Additionally, the members of the
institute present biological problems of
infectious diseases in lectures, seminars
and practical courses in particular to the
students of the Biology department, but
also to a certain extent to medical and dental students. As the education of graduate
students is thereby one of the main
focuses, the Institute for Molecular Infection
Biology has been involved in establishing
the „Graduate School of Life Siences“ at
the University of Würzburg.
The groups at the Institute for Molecular
Infection Biology study several molecular
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
aspects of infections that are caused by
bacteria, parasites and fungi. The research
group ‘Molecular Parasitology and Infectious Immunology’ (headed by Heidrun
Moll) is particularly interested in interactions between parasitic pathogens and
the immune system. The research group
‘Molecular Mycology’ (headed by Joachim
Morschhäuser) investigates disease
processes of fungal infections. The bacteriological research groups study a broad
spectrum of pathogens including enterobacteria, legionellae, Gram-positive bacteria such as staphylococci and enterococci. Both interactions between pathogens and host cells and the dynamic
processes in pathogen variability are
subjects of interest of these groups.
The Institute for Molecular Infection Biology
employs ca. 50 persons that comprise
scientists, graduate students, undergraduates and visiting researchers from
Germany and from abroad. The work is
primarily financed by funds from the Deutsche Forschungsgemeinschaft (DFG), the
Federal Ministry of Education and Research (BMBF), the European Union (EU)
and several other grant organizations.
Members of the institute take responsibility
in positions of the University’s
Fig. 1: Electronmicroscopy of
Enterobacteria
ZINFbericht-final.P65
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56
3. Die Institutionen des Zentrums für Infektionsforschung
3.5.1 Immunological and cell biological
studies on the pathogenicity of Leishmania
parasites (Heidrun Moll)
a)The biogenesis of Leishmania-harboring vacuoles in dendritic cells
In mammalian hosts, Leishmania parasites are obligatory intracellular and invade
macrophages and dendritic cells (DC)
where they reside in endocytic organelles
termed parasitophorous vacuoles (PV).
Most of the present knowledge of the
characteristics of PV harboring Leishmania is derived from studies with infected
macrophages. Since DC play a key role in
host resistance against leishmaniasis,
there is a need to understand the properties
and biogenesis of PV in Leishmaniainfected DC. Therefore, we determined the
acquisition of endosomal and lysosomal
molecules by Leishmania major-containing compartments in DC at different
maturation stages, using fluorescence
labeling and confocal microscopy. The
Heidrun Moll
30. August 1957
Prof. Dr. Heidrun Moll
Institut für Molekulare Infektionsbiologie
Röntgenring 11
D-97070 Würzburg
Germany
Tel.: ++49 (0)931-31 2627
Fax: ++49 (0)931-31 2578
[email protected]
ZINFbericht-final.P65
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results show that newly formed phagosomes in DC rapidly develop into late
endosomal compartments. However, the
small GTPase Rab7, which regulates late
fusion processes, was found only in PV of
mature DC and was absent in immature
DC, suggesting an arrest of their PV
biogenesis at the stage of late endosomes.
Indeed, fusion assays with endocytic
tracers demonstrated that the fusion activity
of L. major-harboring PV towards lysosomes is higher in mature DC than in immature DC. The inhibition of PV-lysosome
fusion in DC is dependent upon the viability
and life cycle stage of the parasite, because
live promastigotes blocked the fusion
almost completely, whereas killed organisms and amastigotes induced a considerable level of fusion activity. The
differences in the fusion competence of
immature and mature DC may be relevant
for their distinct functional activities in the
uptake, transport and presentation of
parasite antigens.
Education and Academic Appointments:
1976-1981 Studies in Biology, University of Konstanz (Diploma)
1982-1985 Doctoral Studies at the Max-Planck-Institute of Immunobiology, Freiburg
1985 Ph.D., University of Konstanz
1986-1988 Postdoctoral fellow, The Walter and Eliza Hall Institute of Medical
Research, Melbourne, Australia
1988-1993 Senior scientist, Institute of Clinical Microbiology and Immunology,
University of Erlangen
1993 Habilitation (Immunology), Medical Faculty of the University of Erlangen
1993-1998 Group leader, Research Center for Infectious Diseases,
University of Würzburg
1995- Professor and Head of the Infection Immunology Unit, Institute for Molecular
Infection Biology, University of Würzburg
2004- Vice President of the University of Würzburg
Selected Awards, Committees, Editorial Boards:
1986-1988 Fellowship of the DFG (German Research Foundation)
2000 Siebold Nagasaki Medical Award
2001- German Society of Parasitology, Board member
2003- German Society of Immunology, Board member
2003- Editorial Board member „Infection and Immunity“
2004- Editorial Board member „European Journal of Cell Biology“
2004- Editorial Board member „Current Immunology Reviews“
2004- Member of Senate Committee and Grants Committee on Research Training
Groups („Senatsausschuss und Bewilligungsausschuss für die
Graduiertenkollegs“), German Research Foundation
2005- German Society of Parasitology, Vice President
Senior Scientists / Postdoctoral fellows:
Prof. Dr. Alicia Ponte-Sucre (since 2004)
Dr. Marcela Fajardo-Moser (since 2004)
Dr. Dr. Katharina Remer (since 2005)
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
b) Identification and characterization of
leishmanicidal compounds
Chemotherapy of leishmaniasis is mainly
based on antimony compounds. However,
their toxicity causes serious side effects.
Moreover, resistance to antimonials is frequent and can reach 50-65 % of the treated
cases in some areas of the world. Secondline drugs are also toxic and require close
clinical control. Finally, current antileishmanial treatments remain extremely
expensive for countries in which the
disease is endemic. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis.
Schemes to develop novel leishmanicidal
drugs include the analysis of naturally
occurring plant-derived compounds, such
as naphthylisoquinoline alkaloids (NIQs),
which were shown to be interesting drug
candidates for the use against Leishmania. Another promising strategy is the
targeting of parasite cysteine proteases
(CPs) which are essential for their growth,
differentiation and pathogenicity. To identify
new leishmanicidal compounds for potential clinical use, we compared the cytotoxic
Lamp1
effects of NIQs and CP inhibitors against
Leishmania major and its major host cells,
macrophages and dendritic cells. Treatment of L. major promastigotes, the
extracellular parasite form, with specific
NIQs and CP inhibitors resulted in dosedependent inhibition of parasite growth
with IC 50 values in the low micromolar
range. Both types of compounds decreased
the infection rate of peritoneal macrophages at concentrations that were 8- to
500-fold lower and, thus, had an even more
potent effect on intracellular Leishmania
amastigotes. CP inhibitors were less toxic
against host cells than NIQs. Furthermore,
CP inhibitors, but not NIQs, were able to
modulate the cytokine secretion and nitric
oxide production by host macrophages. Our
results suggest that the intracellular form
of the parasite is more sensitive to the
compounds and demonstrate that NIQs
and CP inhibitors are promising candidates for further investigation of their
leishmanicidal activity.
L. major
Merge
Fig. 2: Endosomal compartments in DC harbor Leishmania parasites. DC infected for
one hour with L. major that had been prestained with 5-chloromethylfluoresceindiacetat
(CMFDA, green) were subjected to intracellular staining for Lamp1, a marker of late
endosomes/lysosomes, using a phycoerythrin-labeled antibody. The localization of Lamp1
(red, left) and L. major parasites (green, center) was analyzed by confocal microscopy. A
parasite residing in a parasitophorous vacuole that also contains Lamp1 is indicated by
arrows (merge, right). Bar: 5 μm.
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57
Selected references:
- Körner, U., Fuss, V., Steigerwald, J.,
and Moll, H. (2006) The biogenesis of
Leishmania major-harboring vacuoles
in murine dendritic cells. Infect Immun
74: 1305-1312.
- Ponte-Sucre, A., Faber, J.H., Gulder,
T., Kajahn, I., Pedersen, S.E.H., Schultheis, M., Bringmann, G., and Moll, H.
(2007) Activity of naphthyl-isoquinoline
alkaloids and synthetic analogs
against Leishmania major. Antimicrob
Agents Chemother, 51: 188-194.
- Ponte-Sucre, A., Vicik, R., Schultheis,
M., Schirmeister, T., and Moll, H. (2006)
Aziridine-2,3-dicarboxylates: peptidomimetic cysteine protease inhibitors
with antileishmanial activity. Antimicrob
Agents Chemother 50: 2439-2447.
- Moll, H. (2006) Dendritic cells in
leishmaniasis: Regulators of immunity
and tools for new immune intervention
strategies. In: Handbook of Dendritic
Cells – Biology, Diseases and Therapies, M. B. Lutz, A. Steinkasserer and
N. Romani (eds.), Wiley-VCH, Weinheim, Germany, pp. 669-691.
58
3. Die Institutionen des Zentrums für Infektionsforschung
3.5.2 Biology and Pathogenicity of Candida
albicans (Joachim Morschhäuser)
Joachim Morschhäuser
30. März 1963
Prof. Dr. rer. nat.
Joachim Morschhäuser
Institut für Molekulare Infektionsbiologie
Röntgenring 11
D-97070 Würzburg
Tel.: ++49 (0)931-312152
Fax: ++49 (0)931-312578
[email protected]
ZINFbericht-final.P65
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Infections by opportunistic fungi have
become a major medical problem in the
past decades. The yeast Candida albicans
is a harmless commensal in most healthy
people, but it can also cause mucosal as
well as life-threatening systemic infections,
especially in immunocompromised patients. A variety of virulence-associated
characteristics contribute to the capacity of
C. albicans to adapt to and multiply in many
different host niches. These include the
metabolic adaptation to the nutritional
requirements in various host niches
encountered during an infection, the
environmentally regulated transition between the budding yeast form and several
filamentous forms, and the generation of
genetic variants which are better adapted
to permanent alterations in the host
environment, like antifungal drug-resistant
strains.
Our group is characterizing the signals and
signal transduction pathways controlling
morphogenesis, virulence gene expres-
sion, and antifungal drug resistance in
C. albicans. We are studying the role of
ammonium permeases in the induction of
filamentous growth in response to nitrogen
starvation. By comparing C. albicans and
the closely related, but less pathogenic
species C. dubliniensis we identified a
central regulator of chlamydospore formation, a developmental programme
found only in these two species (see Fig.
3). In a project of the SFB 479, we investigate how the switching between the
normal yeast form and a mating-competent, so-called opaque cell form is
regulated in certain C. albicans strains. In
addition, we are analyzing the regulatory
networks controlling the expression of efflux
pumps that are responsible for the
development of antimycotic drug resistance. Another aim, which is the topic of
a project within the SFB 630, is the
identification and functional analysis of
substances that either directly inhibit growth
of C. albicans or block the virulence or
resistance mechanisms of this fungus in
order to develop novel antifungal agents.
Academic career:
1983-1989 Studies of Biology in Frankfurt/Main and Würzburg
1989-1993 Dissertation at the University of Würzburg
1993-1997 Project leader at the Research Center for Infectious Diseases in
Würzburg
1997-2000 Junior group leader at the Research Center for Infectious Diseases in
Würzburg
1999
Habilitation
2001-2002 Heisenberg fellow of the DFG at the Institute for Molecular Infection
Biology, University of Würzburg
2002-2003 Heisenberg fellow of the DFG at the Max-von-Pettenkofer Institute in
München
2004Professor (C3) at the Institute for Molecular Infection Biology,
University of Würzburg
Fellowships and awards:
1991-1993 Doctoral thesis fellowship of the „Studienstiftung des deutschen
Volkes“
1994
Thesis of award of the „Vereinigung für Allgemeine und Angewandte
Mikrobiologie“ (VAAM)
2000
Promotion award of the „Deutsche Gesellschaft für Hygiene und
Mikrobiologie“ (DGHM)
2001-2003 Heisenberg fellowship of the „Deutsche Forschungsgemeinschaft“
2001
Research promotion award of the „Deutschsprachige Mykologische
Gesellschaft“ (DMykG)
2002
Robert Koch promotion award of the Bergstadt Clausthal-Zellerfeld
Senior scientist:
Dr. Peter Staib
23.04.2007, 14:49
3. Institutions of the Research Center for Infectious Diseases
C. albicans wild-type
C. albicans nrglΔ
C. dubliniensis wild-type
Fig. 3: Chlamydospore formation in C. albicans and C. dubliniensis. This developmental programme
is differentially regulated in the two species. While both produce chlamydospores on rice agar, only
C. dubliniensis forms chlamydospores on Staib agar, because it downregulates the NRG1
repressor. C. albicans continues to express NRG1 under these conditions and grows only in the
yeast form, but inactivation of the NRG1 gene results in chlamydospore formation also in C. albicans.
Shown are phase contrast (top panels) and scanning electron micrographs (bottom panels) of a
C. albicans wild-type strain (left), a C. albicans nrg1 mutant (middle) and a C. dubliniensis wildtype strain (right) grown on Staib agar. The arrows point to the large chlamydospores formed at the
tips of pseudohyphae.
Selected references:
- Staib, P., and Morschhäuser, J. (2005)
Differential expression of the NRG1 repressor
controls species-specific regulation of
chlamydospore development in Candida
albicans and Candida dubliniensis. Mol Microbiol
55: 637-652.
- Biswas, K., and Morschhäuser, J. (2005) The
Mep2p ammonium permease controls nitrogen
starvation-induced filamentous growth in
Candida albicans. Mol Microbiol 56: 649-669.
- Reuß, O., and Morschhäuser, J. (2006) A
family of oligopeptide transporters is required
for growth of Candida albicans on proteins. Mol
Microbiol 60: 795-812.
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3. Die Institutionen des Zentrums für Infektionsforschung
Selected references:
-Hochhut, B., Wilde, C., Balling, G.,
Middendorf, B., Dobrindt, U., Brzuszkiewicz, E., Gottschalk, G., Carniel, E.,
and Hacker, J. (2006) Role of pathogenicity island-associated integrases
in the genome plasticity of uropathogenic Escherichia coli strain 536.
Mol Microbiol 61:584-595.
-Nougayrède, J.-P., Homburg, S.,
Taieb, F., Boury, M., Brzuszkiewicz, E.,
Gottschalk, G., Buchrieser, C., Hacker,
J., Dobrindt, and U., Oswald, E. (2006)
Escherichia coli induces DNA double
strand breaks in eukaryotic cells.
Science 313:848-851.
-Brzuszkiewicz, E., Brüggemann, H.,
Liesegang, H., Emmerth, M., Ölschläger, T., Nagy, G., Albermann, K.,
Wagner, C., Buchrieser, C., Emõdy, L.,
Gottschalk, G., Hacker, J., and Dobrindt, U. (2006) Comparative genomic
analysis of extraintestinal pathogenic
Escherichia coli strains reveals how to
become an uropathogen. Proc Natl
Acad Sci USA 103:12879-12884.
3.5.3 Analysis of virulence mechanisms
and genomic diversity of extraintestinal
pathogenic and non-pathogenic Escherichia coli (Ulrich Dobrindt)
Pathogenic enterobacteria cause several
diseases in humans and animals. Extraintestinal pathogenic E. coli are involved
in urinary tract infections, newborn meningitis and sepsis. Some E. coli variants
cause severe systemic infections of
animals. Among different members of the
Enterobacteriaceae and especially among
different E. coli isolates, the genome sizes
vary significantly. DNA acquisition by
horizontal gene transfer as well as loss of
genetic information contribute to the
genetic diversity among Enterobacteriaceae and are important mechanisms
involved in genome optimization of these
organisms.
The group studies processes involved in
genetic diversity and genome optimization
of pathogenic and commensal enterobacteria. Analysis of the underlying
mechanisms will provide us with a better
understanding of the processes involved
in evolution of pathogenic bacteria. For this
purpose, we use the uropathogenic E. coli
strain 536 as well as the non-pathogenic
E. coli strain Nissle 1917 as model
organisms to analyze the genome organization, distribution of virulenceassociated genes as well as their function
and expression. The complete genome
sequence of strain 536 is included into
comparative analyses of complete genome sequences of other pathogenic and
non-pathogenic E. coli strains and other
enterobacteria in order to identify factors
which may be responsible for the different
diseases observed. The unstability of PAIs
and the role of PAI-encoded bacteriophage
integrases for PAI deletion is studied in
detail as well as regulatory networks
involved in virulence gene regulation.
Furthermore, we aim at the functional
characterization of novel virulence-associated genes in extraintestinal pathogenic
E. coli. The group also focusses on factors
and mechanisms contributing to multicellular behaviour and biofilm formation
of extraintestinal pathogenic E. coli.
Fig. 4: Mechanisms involved in
bacterial genome optimization.
Ulrich Dobrindt
07. Juli 1970
AR Dr. rer. nat. Ulrich Dobrindt
Institut für Molekulare Infektionsbiologie
Röntgenring 11
97070 Würzburg
Tel.: ++49 (0)931 312155
Fax: ++49 (0)931 312578
[email protected]
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Scientific career:
1989-1995 Study of Biology in Göttingen
1999 PhD thesis at the Institute for Molecular Infection Biology,
University of Würzburg
1999 Research assistant at the Institute for Molecular Infection Biology
Functions, distinctions:
1996-1998 PhD scholarship of the Boehringer Ingelheim Fonds
2001- Group leader (E. coli Pathogenomics)
2004 Promotion award (Förderpreis) of the German Society for Hygiene and
Microbiology (Deutsche Gesellschaft für Hygiene und Mikrobiologie)
Scientific coworkers:
Dr. Caroline Wilde
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3.5.4 Bacterial Adhesins and Invasins-Early
steps in bacterial infection and countermeasures (Tobias Ölschläger)
An early essential step in the establishment of bacterial infections is adhesion to
host surfaces mediated by fimbriae/pili or
afimbrial adhesins. Expression of these
bacterial surface structures interferes with
mechanical action of the host aimed at
removing bacteria. Therefore, adherence
is a common property of bacteria able to
colonize or infect macroorganisms e.g
humans. In addition, several pathogenic
bacteria are not only restricted to host
surfaces but are able to invade host cells
and survive intracellularly. Such bacteria
have made themselves available a privileged niche where they are protected form
the host’s immune system and the action
of many antibiotics. Members of this group
of bacteria are several E. coli pathotypes,
Salmonella, Shigella, Listeria and Mycobacterium tuberculosis. As diverse as
these bacteria are their invasion systems.
Elucidation of the molecular fundamentals
of these interactions (adhesion and
invasion) promises to form the basis for
new antiinfective preventions.
The research group screens selected
carbohydrates for the ability to interfere with
bacterial adherence to and/or invasion into
host cells of several E. coli pathotypes,
Salmonella and Shigella. In vitro host cell
models employed are human urinary tract
and gut epithelial cell lines and cryosections of human gut biopsies. In ad-dition
the mouse model was used.
Besides mechanisms of molecular pathogenicity the machinery of probiotics to
counteract these is investigated. For that
purpose the Escherichia coli strain Nissle
1917 (EcN) was chosen as a model for
probiotic bacteria, because its efficacy was
demonstrated in clinical trials and it has
an excellent safety record. We could
demonstrate in vitro antiinvasive activity of
EcN for Salmonella, Shigella, Yersinia and
Listeria. The antiinvasive effect is EcNdose dependent and relies on live EcN.
The active compound seems to be secreted by EcN. By screening a BAC-library,
the determinant for this activity was cloned
and sequenced. Additionally, the flagellin
was identified as the inducing factor for
human b-defensin 2 expression in Caco-2
cells. Further studies are directed to gain
more insight into properties of EcN related
to its probiotic nature.
61
Selected references:
- Alpert, C., Engst, W., Gühler, A.,
Oelschlaeger, T.A., and Blaut, M. (2005)
Bacterial response to eukaryotic cells:
analysis of differentially expressed
proteins using nano liquid chromatography-electrospray ionization tandem
mass spectrometry. J Chromatography
1082: 25-32.
- Schultz, M., Watzl, S., Oelschlaeger,
T.A., Rath, H.C., Göttl, C., Lehn, N.,
Schölmerich, J., and Linde, H.-J.
(2005) Green fluorescent protein for
detection of the probiotic microorganism Escherichia coli Nissle 1917
(EcN) in vivo. J Microbiol Meth 61: 389398.
Fig. 5: The scanning electronmicroscopical
image of non-pathogenic E. coli bacteria
Scientific career:
1975 - 1980 Studies in Biology at the Albert-Ludwigs University in Freiburg i.Br.
and Eberhard-Karls University of Tübingen
1986 Dissertation at the Eberhard Karls University of Tübingen
1986 - 1990 Research fellowship at the Institute of Microbiology II (Prof. V. Braun)
University of Tübingen
1990 -1992 Research fellowship of the DFG at the Walter Reed Army Institute
of Research, Washington, DC, SA, (Dr. D.J. Kopecko)
1992-1994 Senior Research Fellow of the National Research Councils of
National Academie of Sciences, Washington, DC, USA
1994 Research Group leader at the Institute for Molecular Infection Biology,
University of Würzburg
1997 Appointment for life as „Akademischer Rat“
Tobias Ölschläger
21. März 1952
Dr. rer. nat. Tobias Ölschläger
Institut für Molekulare Infektionsbiologie
Röntgenring 11
97070 Würzburg
Telefon: ++49 (0)931 312150
Fax: ++49 (0)931 312578
[email protected]
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3.5.5 Molecular and cellular studies on the
pathogenicity of Legionella pneumophila
(Michael Steinert, Klaus Heuner)
Legionella pneumophila is naturally found
in fresh water were the bacteria parasitize
intracellularly within protozoa. Upon aerosol
formation via man-made water systems,
L. pneumophila can enter the human lung
and cause a severe form of pneumonia,
called Legionnaires´ disease. Our working
group studies the pathogenicity of Legionella as well as the host side of infection.
Moreover we analyze the genome structure
and regulatory networks of this pathogen.
In these studies we mainly focus on
specific virulence factors like the peptidylprolyl cis/trans isomerase Mip (macrophage infectivity potentiator), a cell associated phospholipase (PlaB), a type I secretion system (Lss, Legionella secretion
system), a new putative conjugation
system (type IVA secretion system) and the
Klaus Heuner
08. Juni 1967
Academic career:
1988-1994 Study of Biology in Würzburg
1994-1997 Dissertation at the Institute for Molecular Infection Biology,
University of Würzburg
1997-2000 Post-Doc at the Institute for Microbiology and Hygiene of the
Humboldt-University of Berlin (Universital hospital, Charité)
Since 2000 Research group leader at the Institute for Molecular Infection
Biology, University of Würzburg
2007
Habilitation in Microbiology, Faculty of Biology, Würzburg
Fellowships and Awards:
1994-1996 Doctoral thesis fellowship „Graduate College: Infektiologie“ (DFG)
2000-2002 Post doctoral fellowship „European Graduate College: Gene
regulation in and by microbial pathogens“ (DFG)
regulatory link of virulence and flagellation.
In order to dissect the complex host-pathogen cross talk we have developed
custom tailored surrogate host systems
and tissue models. In this regard the
genetically tractable Dictyostelium model
and the lung epithelial barrier system
proved to be particulary useful.
Research topics
a) By using comparative genomic approaches we were able to reveal genetic
differences between virulent and avirulent
Legionella strains. Moreover, it became
evident that L. pneumophila encodes a
high number of eukaryotic-like proteins
which reflects the close association of
legionellae with host cells. Subsequent
applications of DNA microarrays have
already provided first insights into the
intracellular gene expression patterns of
L. pneumophila. A primary goal of this
project is to unravel those genes that are
essential for the manifestation of Legionnaires´ disease.
b) In a second project we analyze various
pathogenicity factors of L. pneumophila.
Here we mainly focus on the cell associated phospholipase (PlaB) and the
regulatory link of virulence and bacterial
flagellation. We were able to show that the
flagellum is a virulence associated factor
and that the expression of the virulent
phenotype (transmissive phase)
and motility are regulated coordinately (Fig. 6). The master
regulator of the flagellar regulon is
FleQ. Further investigations revealed that FliA and RpoN were
also involved in the regulation of
genes encoding the filament strucFig. 6: The proposed cascade
for regulation of virulence and
the flagellum of L. pneumophila. The model correlates
with the transition of L. pneumophila from the replicative
(„non-virulent“) to the transmissive („virulent“) phase.
Positive (+) and negative (-)
regulation is indicated by
arrows. Dotted lines indicate
that the mode of action is not
known yet. S 54, alternative
sigma-54 factor.
Dr. rer. nat. Klaus Heuner
Institut für Molekulare Infektionsbiologie
Röntgenring 11
97070 Würzburg
Tel.: ++49 (0)931-312151
Fax: ++49 (0)931-312578
[email protected]
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ture, the basal body and the assembly of
the flagellum.
c) A third project is dedicated to Legionella
virulence factors which are transported to
their targets via secretion systems. We
recently identified a first putative type I
secretion system encoded by the lss locus
(Lss, Legionella secretion system) of L.
pneumophila. Using 2 D gel electrophoresis and an lssB mutant strain of L.
pneumophila Corby we identified a LssBdependent secreted protein of approximately 15 kDa. The identified protein
exhibits a VirK_Pfam domain. We also
were able to identify a putative new
conjugation/ type IV secretion system
encoded by a genomic island of approximately 43 kb. The genomic island is
excised from the chromosom and then able
to be transferred to another Legionella
strain by conjugation.
d) Wheather or not host organisms
become infected by pathogens is the result
of a complex interplay between host and
pathogen genotypes, as well as the
physiological condition of both species. In
order to also analyze the host side of
infection we established a genetically
tractable Dictyostelium host model of
Legionella infection and an in vitro lung
epithelial barrier system. The analysis of
the intracellular growth, subcellular localization and the intracellular activites of
Legionella suggested that Dictyostelium is
a representative host-model system. By
using mutants of the haploid amoeba
Dictyostelium discoideum we were able to
identify infection relevant host cell factors
and signal transduction pathways. The use
of a newly developed lung epithelial barrier
system enabled us to study the tissue
invasion of Legionella into the lung. We
63
found that the Legionella Mip protein binds
to collagen which renders this component
sensitive for cleavage by a serine protease.
This activity finally contributes to the
perforation of the lung epithelial barrier in
vitro and in vivo (Figure 7). Drug developments to block this mechanism could be
an entirely new approach to treat Legionnaires´ disease and might have further applications for other pathogens.
Selected references:
- Brüggemann, H., Hagman, A., Jules, M.,
Sismeiro, O., Dillies, M.-A., Gouyette, C.,
Kunst, F., Steinert, M., Heuner, K., Coppee, J.Y., Buchrieser, C. 2006. Virulence strategies
for infecting phagocytes deduced from the
transcriptional program of Legionella pneumophila. Cell. Microbiol. 8: 1228-1240.
- Steinert, M., Heuner, K. 2005. Dictyostelium
as host model for pathogenesis. Cell. Microbiol.
7: 307-314.
Michael Steinert
05. Juni 1966
Academic career:
1985-1992 study of Biology in Würzburg
1992-1996 PhD at the University of Würzburg
1996-1998 Postdoc at the Centers for Disease Control and Prevention, Atlanta,
GA, USA
1998Research group leader at the Institute for Molecular Infection
Biology, University of Würzburg
2003
Habilitation at the Faculty of Biology, University Würzburg
2006
Offer of W2 professorship in Braunschweig (accepted)
Fellowships and Awards:
1996-1998 Fellowship of the DFG (German Research Foundation
Fig. 7: Histopathology of lung tissue sections
and distribution of Mip-positive and Mipnegative L. pneumophila strains after intratracheal infection of guinea pigs. The infection
with the Mip-positive strain results in a
confluent bronchopneumonia with an extensive
neutrophilic infiltration of the alveolar parenchyma.
PD Dr. rer. nat. Michael Steinert
Institut für Molekulare Infektionsbiologie
Röntgenring 11
97070 Würzburg
Tel.: ++49 (0)931-312588
Fax: ++49 (0)931-312578
[email protected]
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3.5.6 Virulence and resistance mechanisms of pathogenic staphylococci
(Knut Ohlsen, Wilma Ziebuhr)
Staphylococcus aureus and Staphylococcus epidermidis are the most common
causative agents of device-associated
nosocomial infections in immunocompromised patients and the extraordinary
high resistance rate towards many commonly used antibiotics pose a great
challenge for the management of these
infections. The Staphylococcus research
group investigates factors and processes
which are associated with the pathogenesis of staphylococcal diseases and
contribute to the establishment of these
bacteria in the hospital environment.
Staphylococci are very flexible microorgansisms exhibiting a broad phenotypic
and genetic variability. Specifically in S.
epidermidis, the ability to form biofilms on
smooth artificial surfaces is a typical feature
of pathogenic strains whose expression
undergoes phenotypic variation. Staphylococcus biofilm formation is influenced by
external factors and regulatory processes
as well as by genetic mechanisms such
as phase variation, deletions, mutations
and genome rearrangements which are
associated with the action of insertion
sequences (i.e. IS256). Epidemiological
studies revealed that IS256 is a common
constituent of the genome of pathogenic
Staphylococcus aureus and Staphylo-
coccus epidermidis. The element is highly
active and causes reversible gene inactivations as well as induction of neighbouring gene expression. Moreover, multiple IS256 copies can function as crossover points for homologous recombination
events and contribute therefore to the
instability of the staphylococcal genome.
Thus, IS256 seems to represent an
important factor for the generation of
genotypic and phenotypic diversity in these
bacteria. The data sugest that the pathogenic potential of a bacterium is not only
associated with the presence or abscence
of virulence factors. In fact, the ability to reorganize the existing genetic material and
to permanently modify its expression is an
Fig. 8: Biofilm formation of Staphylococcus
epidermidis on a polystyrene surface.
Tel.: ++49 / 931 -312154
Academic career:
1984-1991 Studies of Medicine; Friedrich-Schiller-Universität Jena
1990-1991 Diploma thesis at the Institute for Clinical Immunology of the University of
Jena
1991
State examination
Scientific work and positions:
1991-1994 Grant of the „Deutsche Forschungsgemeinschaft“
1994
Doctoral thesis at the Institute for Molecular Infection Biology,
University of Würzburg
1996
Doctorate award of the Medical Faculty of the Würzburg University
1994-1996 Postdoc fellow at the Institute for Medicinical Microbiology of the FriedrichSchiller-University, Jena
1996
Group leader at the Institute for Molecular Infection Biology,
University of Würzburg
2003
Habilitation (lecture qualification) for the subject „Molecular Biology of
Infectious Diseases“
2006
Offer and Acceptance of the „Reader in Bacteriology“ Postition at the
University of Belfast
Fax. ++49 / 931 - 312578
Senior scientist:
[email protected]
Dr. Swetlana Kozitskaya
Wilma Ziebuhr
21. Oktober 1964
PD Dr. med. Wilma Ziebuhr
Institut für Molekulare Infektionsbiologie
Universität Würzburg
Röntgenring 11
D-97070 Würzburg
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evolutionary advantage which seems to be
efficiently utilized by Staphylococci. The
action of IS elements is an imortant driving
force in this process enabling the bacteria
to adapt to changing environmental conditions and to conquer new ecological
niches.
A major research topic deals with the
exploration of virulence mechanisms in
staphylococci. Recently, a catheter-related
infection model in rats was established.
Using this animal model system pathogenesis of catheter-related infections can
be studied in vivo. First, we investigated
the impact of the alternative sigma factor
SigB on biofilm formation in vivo and on
the infectious process. The experiments
revealed that sigB deficient bacteria were
able to form a biofilm inside the catheter
lumen, but they were significantly attenuated in virulence. Further work using this
model aims at the investigation of the role
of global regulatory molecules such as agr
and arl and general fitness factors for the
virulence of the organisms. For this
purpose, full genome DNA microarrays of
S. aureus and S. epidermidis were developed which are now employed both for
gene expression analyses of regulatory
mutants and genome comparison studies
of pathogenic variants. The approach is
completed by investigation of the protein
expression patterns using two–dimensional protein gelelectrophoresis. The long
term goal of this comprehensive approach
is a better understanding of Staphylococcus gene regulation which will in turn
lead to the identification of novel targets for
future antibiotic therapies.
65
Selected references:
- Batzilla, C.F., Rachid, S., Engelmann, S.,
Hecker, M., Hacker, J., and Ziebuhr, W. (2006)
Impact of the Accessory Gene Regulatory
System (Agr) on Extracellular Proteins, codY
Expression and Amino Acid Metabolism in
Staphylococcus epidermidis. Proteomics
6:3602-3613.
- Ziebuhr, W., Hennig, S., Eckart, M., Kränzler,
H., Batzilla, C., Kositzkaya, S. (2006) Nosocomial infections by Staphylococcus epidermidis: how a commensal bacterium turns
into a pathogen. Int J Antimicrob Agents 28:1420.
- Hauck, C.R., and Ohlsen, K. (2006) Sticky
connections: extracellular matrix protein
recognition and integrin-mediated cellular
invasion by Staphylococcus aureus. Curr Opin
Microbiol 9:1-7.
- Agerer, F., Lux, S., Michel, A., Rohde, M.,
Ohlsen, K., and Hauck, C.R. (2005) Cellular
invasion by Staphylococcus aureus reveals a
functional link between focal adhesion kinase
and cortactin in integrin-mediated internalisation. J Cell Sci 118:2189-2200.
Academic career:
1988-1993 Study of biology at the University of Leipzig
1993-1997 PhD student at the Institute for Molecular Infection Biology,
University of Würzburg, Germany
1997-1998 Postdoctoral fellow at the Institute for Molecular Infection Biology,
University of Würzburg
1997
PhD thesis at the Institute for Molecular Infection Biology
1998Group leader, at the Institute for Molecular Infection Biology
Knut Ohlsen
29. Mai 1966
Dr. rer. nat. Knut Ohlsen
Institut für Molekulare Infektionsbiologie
Röntgenring 11
Senior scientist:
Dr. Christian Hüttinger
97070 Würzburg
Tel.: ++49 (0)931 312155
Fax: ++49 (0)931 312578
[email protected]
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3.5.7 Molecular characterization of pathogenic reactions of Entamoeba histolytica
(Heike Bruhn)
The protozoon Entamoeba histolytica is
the causative agent of human amoebiasis, the second leading cause of death
due to parasite infections. 50 Million
people are infected and approximately 100
000 of them die annually. Due to the fecaloral path of infection, the disease is mostly
prevalent in developing countries under
insufficient hygienic conditions. The
amoeba lives as a commensale in the
human colon feeding here on bacteria.
Occasionally, it will cross the mucosa in
an active locomotion and may invade into
the tissue thereby - true to its name –
exciting severe tissue destruction, which
mostly result in serious liver abscesses.
The killing of human cells is mainly
provoked by a family of membranepermeabilising proteins termed amoebapores. The mechanism of their disruptive
activity is the formation of stabile oligomers leading to pores of a defined size,
as could be evidenced by a combination
of biochemical characterization and
structural analysis. The amoebapores are
the first cytolytic representatives of this
protein family, the saposin-like proteins
(SAPLIPs), and also its first known
protozoan members. The recently published genome sequence of E. histolytica
revealed 16 SAPLIP sequences in addition
to the three amoebapores. Beside putative
defense molecules with amoebapore-like
activities, some of these proteins are
involved in membrane-trafficking and
Heike Bruhn
07. April 1965
Dr. rer. nat. Heike Bruhn
Zentrum für Infektionsforschung
Röntgenring 11
D- 97070 Würzburg
Germany
Tel.: ++49 (0)931 312141
Fax: ++49 (0)931 312578
[email protected]
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reorganization during phagocytosis. The
extraordinary number of these proteins in
such a primitive organism indicates an
essential importance for the survival and
development of the amoeba. The uniqueness of sequence and architecture of
these proteins without homologues in any
known genome including the human host
raises hope of their applicability for
urgently needed novel antiparasitic drugs.
Fig.9: E. histolytica trophozoites filled with phagozytosed human erythrozytes.
Selected references:
- Winkelmann J, Leippe M, Bruhn H (2006): A
novel saposin-like protein of Entamoeba
histolytica with membrane-fusogenic activity.
Mol Biochem Parasitol 147:85-94
.
- Bruhn H (2005): A short guided tour through
functional and structural features of saposinlike proteins. Biochem J 389:249-57 .
- Leippe M, Bruhn H, Hecht O, Grötzinger J
(2005): Ancient weapons: the three-dimensional structure of amoebapore A. Trends
Parasitol 21:5-7
Education and Experience:
Since 2001 Research assistant at the Reserach Center for Infectious
Diseases, Würzburg
2007
Habilitation in microbiology
1998–2001 Research assistant at the Bernhard Nocht Institute for Tropical
Medicine, Hamburg
1995–1998 Postdoctoral fellow at the Gene Center, Ludwig-Maximilians
University of Munich
1995
PhD degree of the Heinrich Heine University of Düsseldorf
1984 – 1990 Study of Chemistry at the University of Köln
Responsibilities and Awards:
2006–2007 Fellowship for excellent young investigators of the Federal
Government and „Länder“
2001–2004 Fellowship of the „higher education and science
programme“ (HWP) of the Federal Government and „Länder“
since October 2003 - Project group „Molecular Parasitology“
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3. Die Institutionen des Zentrums für Infektionsforschung
3.6 Pathologisches Institut
Hans-Konrad
Müller-Hermelink
21. Juni 1943
Prof. Dr. med. H. K.Müller-Hermelink
Vorstand des Pathologischen Institutes
der Universität Würzburg
97080 Würzburg,
Josef-Schneider-Str. 2
Tel. ++49 (0) 931 201-47776
Fax: ++49 (0) 931 201-47440
[email protected]
Die Infektion der Magenschleimhaut mit
Helicobacter pylori (H. pylori) stellt eine der
weltweit am häufigsten vorkommenden bakteriellen Infektionskrankheiten des Menschen dar. H. pylori kolonisiert den Schleim
über dem Magenepithel und führt zur Ausbildung einer entzündlich-immunologischen
Wirtsreaktion der Magenmu-kosa, die als
chronisch aktive Gastritis bezeichnet wird.
Am Pathologischen Institut wird in einem DFG
geförderten Projekt (EC 203/01) in der
Arbeitsgruppe um Matthias Eck und Bernd
Schmaußer die entzündlich-immunologische
Wirtsreaktion bei der H. pylori Infektion untersucht. Diese moduliert zusammen mit
Pathogenitätsfaktoren von H. pylori die
Krankheitsausprägung in der Magenschleimhaut beginnend von der chronisch
aktiven Gastritis, dem Magen- und Duodenalulcus bis hin zum Magenkarzinom und
MALT-Lymphom. Eine wesentliche Rolle spielen hierbei das Chemokin/ Chemokinrezeptorsystem als auch Rezeptoren der
„innate immunity“, z.B. Toll-like Rezeptoren..
In der H. pylori Gastritis konnte die Arbeitsgruppe zeigen, dass CXC-Chemokine das
Entzündungsinfiltrat in der Magenschleimhaut modulieren. Die Chemokine IL-8 und
Groa, werden durch H. pylori in den Epithelzellen induziert werden und spielen eine
wichtige Rolle bei der Wanderung der neutrophilen Granulozyten von den Schleimhautgefäßen in das Magenepithel., während
IP-10 und MIG, die in Makrophagen exprimiert
werden, über den korrespondierenden
Chemokinrezeptor CXCR3 zur Rekrutierung
der inflammatorischen T-Zellen in die Mucosa
beitragen.
Im Magenkarzinom besteht ebenfalls ein
Scientific career:
1962- 1968 Studies of Medicine at the Universities of Tübingen, Montpellier and Kiel
1968 Internship (Medizinalassistent), Institute of Pathology of the University of Kiel
1969 Internship, Universitäts-Frauenklinik Kiel, Medizinische Universitäts-Klinik
Kiel und Chirurgische Universitätsklinik im Krankenhaus Westend, Berlin.
1970 M.D.
1976 Habilitation in Pathology
Faculty and Hospital Positions:
1970- 1985 Affiliated at the Institute of Pathology, University of Kiel
1985 Professor of Pathology and Head of Department, University of Würzburg.
1991 - 1994 Dean of the Medical Faculty, University of Würzburg.
1991 - 1998 Speaker of SFB 172 „Molecular Mechanisms of Cancerogenesis“
1996 Speaker of the Interdisciplinary Center of Clinical Research, Würzburg (IZKF)
1998 - Speaker (together with Prof. E. Serfling) of DFG Research Group: „Altered
Transcription in Lymphoid Tumours“.
2000 Speaker of the GraduateCollege 639 of the DFG „Mechanisms of Tumor
Instability“
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komplexes Zusammenspiel zwischen CXCChemokinsignalen, die sowohl von den
Tumorzellen selbst als auch von den tumorinfiltrierenden Immunzellen abstammen. Diese Chemokinsignale scheinen vielgestaltige
Effekte in der Tumorbiologie (Tumorangiogenese, Wachstumsmuster) zu haben, die
weit über ihre Funktion als reine chemotaktische Moleküle hinausgehen.
Zusätzlich zu der Chemokinexpression selbst
werden nach unseren Daten auch die Expression der Chemokinrezeptoren durch H. pylori
moduliert. So wird der CCR7 Rezeptor auf
dem Magenepithel und auf Magenkarzinomen
exprimiert und durch H. pylori hochgeregelt.
Dies ist von besonderem Interesse, da CCR7
eine wichtige Rolle in der Metastasierung von
Karzinomen spielt.
Aber nicht nur auf dem Magenepithel, sondern auch auf neutrophilen Granulozyten in
der chronisch aktiven Gastritis führt H. pylori
zu einer Regelung von Chemokinrezeptoren.
Dabei konnte die Arbeitsgruppe zeigen, dass
H. pylori den CXCR1- und CXCR2-Rezeptor
auf neutrophilen Granulozyten herunterreguliert. Diese Rezeptorherunterregulierung
erfolgt über einen IL-8, TNF-α und H. pylori
LPS unabhängigen neuen Mechanismus und
ist auf mRNA Ebene abhängig von der CagPathogenitätsinsel. Die Herunterregulierung
des CXCR1- und CXCR2-Rezeptors auf
neutrophilen Granulozyten durch H. pylori
scheint einen neuen Pathomechanismus
während der H. pylori Infektion darzustellen,
der Migration und Aktivierung von neutrophilen
Granulozyten in der Magenmukosa beeinflußt.
Weiterhin werden die Toll-like Receptoren
(TLRs) in den H. pylori assoziierten Erkrankungen untersucht. TLRs können im Gegensatz zu den Chemokinrezeptoren direkt bakterielle Liganden erkennen und so das
Society Membership:
Bavarian Society of Gastroenterology.
European Association of Hematopathology.
European Society of Pathology.
German Cancer Society.
German Society of Pathology.
German-Austrian Society of Hematology and
Oncology.
International Academy of Pathology, British Division
International Academy of Pathology, German
Division
Society of Hematopathology
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
Chemokin/ Chemokinrezeptorsystem und die
nachfolgende immunologische Antwort beeinflussen.
Es konnte gezeigt werden, dass sowohl das
Magenepithel in der H. pylori Gastritis als auch
Magenkarzinomzellen selbst TLRs exprimieren
und somit mit H. pylori interagieren können. Die
TLR Expression im Magenepithel ist polarisiert
in apikales oder basolaterales epithelialen Zellkompartiment und wird dynamisch durch
H. pylori beeinflusst. Dies weist auf eine zentrale Rolle der TLRs in der mukosalen Immunantwort gegen H. pylori hin.
Um eine direkte Rolle von H. pylori in der Entstehung des Magenkarzinoms näher zu charakterisieren, gehen wir in einem weiteren DFG geförderten Projekt interdisziplinär in Zusammenarbeit mit dem Institut für Toxikologie der Frage
einer direkten Gentoxizität von H. pylori nach.
Mittels in vitro micronucleus assay fanden sich
Hinweise auf einen durch H. pylori induzierten
DNA Schaden. In laufenden Untersuchungen soll
geklärt werden, ob H. pylori Virulenzfaktoren wie
z.B. CagA oder H. pylori Stämme aus verschiedenen geographischen Regionen mit unterschiedlicher Karzinomhäufigkeit diese Mikrokernbildung beeinflussen.
3.6 Institute of Pathology
Infection of the gastric mucosa with H. pylori is
one of the most common infections worldwide
in human beings. H. pylori colonizes the
mucous overlying the gastric epithelium
leading to an inflammatory host response in
the gastric mucosa called chronic active
gastritis.
At the Institute for Pathology the mucosal immune response in H. pylori infection is studied
by the group of Matthias Eck and Bernd
Schmaußer. The interplay between H. pylori and
the host modulates the development of
disease in the gastric mucosa starting from
chronic active gastritis and gastric or duodenal
ulceration until the gastric carcinoma and MALTtype lymphoma. In this context the chemokine/
chemokine-receptor system and receptors of
the innate immunity e.g. Toll-like receptors play
an important role.
In H. pylori gastritis the group has demonstrated that CXC-chemokines modulate the
inflammatory infiltrate in the gastric mucosa.
The chemokines IL-8 and Groa, which are
induced by H. pylori, seem to play the central
role in the migration of neutrophils from
mucosal vessels into the gastric epithelium,
whereas IP-10 and MIG contribute via the
corresponding receptor CXCR3 to the re-
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cruitment of inflammatory T-cells into the
mucosa.
In gastric carcinoma also a complex interplay
between CXC chemokines exists, which derive
as well from tumor cells as from tumorinfiltrating
immune cells. These chemokine signals have
pleiotropic effects in tumorbiology (tumor
angiogenesis, growth pattern) far beyond
chemotaxis.
According to our data not only chemokines, but
also chemokine receptors are regulated by
H. pylori. The CCR7 receptor is expressed on
gastric epithelium and on gastric carcinoma cells
and is upregulated by H.pylori. This may be
important as CCR7 plays a crucial role in the
metastasis of carcinoma.
However, H. pylori regulates chemokine receptors expression not only on gastric epithelium,
but also on neutrophils in chronic active gastritis.
The group could demonstrate that H. pylori
downregulates the CXCR1 and CXCR2 receptor
on neutrophils. This down-regulation results by
a new mechanism independend of IL-8, TNF-a
and H. pylori LPS and is on mRNA level
dependend on the cag pathogenicity island.
Downregulation of the CXCR1 and CXCR2
receptor on neutrophils may present a new
pathomechanism in H. pylori infection, which
influences migration and activation of neutrohils
in the gastric mucosa.
In further studies Toll-like receptors (TLRs) in
H. pylori associated diseases were investigated.
In contrast to chemokine receptors TLRs
recognice bacterial ligands and influence the
chemokine/chemokine receptor system and the
resulting immune response by this way.
It has been shown that as well gastric epithelium
in H. pylori gastritis as tumor cells of gastric
carcinoma themseves are able to express TLRs,
which enables them to interact with H. pylori.
TLR expression of gastric epithelium is highly
polarized in apical and basolateral cell compartments. This polarization is dynamically
influenced by H. pylori indicating a central role of
TLRs in the mucosal immune response directed
against H. pylori.
To invesigate a direct role of H. pylori in gastric
carcinogenesis, we evaluate in another DFG
sponsored research project in cooperation with
the Institute for Toxicology the genotoxicity of H.
pylori. By in vitro micronucleus assay we were
able to detect DNA damage induced by H. pylori.
In current studies the group is going on to clarify
whether H. pylori virulence factors as CagA or H.
pylori strains from different geographical regions
with varying carcinoma incidence influence this
micronucleus formation.
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3.7 Medizinische Klinik und
Poliklinik I
Professor Dr. Georg Ertl
Medizinische Universitätsklinik
Würzburg
Josef-Schneider-Str. 2
97080 Würzburg
Tel.: ++49 -(0)9 31-2013 63 00
Georg Ertl
Fax: ++49 -(0)9 31-20136302
12. Juni1950 in Neuburg/ Rhein
[email protected]
1956 - 1968
Primary school in Neuburg, Highschool in Karlsruhe
1968 – 1974
Medical student in Mainz and Graz
1974 – 1975
Internal medicine in Pfronten (surgery) and the University Hospital of Mainz (internal medicine)
1975
Medical Doctor (M.D.) at the University of Mainz
1975 – 1976
Military Service as Medical Officer (compulsory)
1977 – 1979
Research fellow at the Physiological Institute, University of Düsseldorf (Professor Dr. Dr. W. Lochner)
1979 – 1980
Research fellow (Deutsche Forschungsgemeinschaft) at the Harvard University and
Peter Bent Brigham Hospital, Boston, USA (Professor Dr. Braunwald)
1981
Resident for internal medicine at the Medical University Hospital of Würzburg (head: Professor Dr. K. Kochsiek)
1986
„Privatdozent“ (assistant professor) at the medical faculty of Würzburg, internist, assistant medical director and head
of the intensive-care unit for internal medicine
1987
Cardiologist
1991 – 1994
Associate professor (C3) and vice director of the Department of Internal Medicine, University Hospital Würzburg
1995 – 1998
Chairman of Cardiology at the Faculty of Clinical Medicine Mannheim of the University of Heidelberg and Director of the
Department of Internal Medicine at the Hospital of Mannheim, medical vice director of the Hospital of Mannheim
Since 1999
Chair of Internal Medicine and Director of the Department of Internal Medicine, University of Würzburg
2004-2006
Dean of the Medical Faculty of the University of Würzburg
Commissions:
Dean of the medical faculty of the University of Würzburg 2004 - 2006
Member of the managing board of the Medizinische Universitätsklinik 2004 - 2006
Member of the board of the Deutsche Gesellschaft für Kardiologie (German Association of Cardiology)
Speaker of the Sonderforschungsbereich SFB 355 „Pathophysiologie der Herzinsuffizienz“ (Pathophysiology of Heart Failure) – 2004; ViceSpeaker of the Sonderforschungsbereich SFB 688 „Kardiovaskuläre Zell-Zellinteraktionen“ and of the BMBF Kompetenznetz „Herzinsuffizienz“
Memberships:
Deutsche Akademie der Naturforscher, Leopoldina, American Federation for Medical Research
American Association for the Advancement of Science, American Society of Physiology
Council of Basic Science of American Heart Association
Deutsch-Chinesische Gesellschaft für Medizin e.V., Deutsche Gesellschaft für Innere Medizin (Vorsitzender 2007/2008),
Deutsche Gesellschaft für Herz- und Kreislaufforschung (Vorstandsmitglied)
Deutsche Gesellschaft für internistische Intensivmedizin, Vorstandsmitglied der Deutschen Herzstiftung e.V. – 2004.
Deutsche Physiologische Gesellschaft, Europäische Gesellschaft für Kardiologie („Fellow“)
European Society for Magnetic Resonance in Medicine and Biology (ESMRMB), Gesellschaft für Fortschritte in der Inneren Medizin
Grants and Awards:
- Kompetenznetz Herzinsuffizienz BMBF (Network of Competence „Heart Failure“)
- Interdisziplinäres Netzwerk Herzinsuffizienz BMBF (Interdisciplinary Network „Heart Failure“)
- Sonderforschungsbereich SFB 688 „Kardiovaskuläre Zell-Zellinteraktionen“
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3. Institutions of the Research Center for Infectious Diseases
3.7.1 Untersuchungen zum Einfluss der
mikrobiologischen Mundflora auf die
Inzidenz eines akuten Myokardinfarktes
(MUNDART – Studie):
Untersuchungen der letzten Jahre konnten
eine Verbindung zwischen Atherosklerose,
koronarer Herzkrankheit, Herzinfarkt und
Parodontitis aufzeigen. Patienten, die an
einer Parodontitis leiden, zeigen ein 1,5fach erhöhtes Risiko für koronare Herzerkrankungen (KHK), 2,2-fach für letale
KHK und 2,8-fach für Schlaganfall, respektive. Die biologischen Grundlagen
sind zur Zeit aber noch unklar. Ziel der
vorliegenden Studie ist es, Patienten nach
akutem Myokardinfarkt serologisch und
mikrobiologisch auf das Vorhandensein
von Zeichen einer akut abgelaufenen Entzündung mit den wichtigsten parodontopathogenen Bakterien Actinobacillus
actinomycetem-comitans (Aa), Porphyromonas gingivalis (Pg), Treponema
denticola (Td), Bacteroides forsythus (Bf),
Eikenella corrodens (Ec) und Spirochäten
zu untersuchen. Der mikrobiologische
Status dieser Patienten wird mit dem einer
Probandengruppe gleicher Alters- und
Geschlechtsverteilung verglichen, die bei
einer Herzkatheteruntersuchung keine
Anzeichen einer koronaren Herzkrankheit
aufweist. In dieser randomisierten prospektiven Studie sollen 160 Patienten an
den Universitätsklinika Würzburg und
Münster eingeschlossen werden, gegenwärtig sind bereits 89 Patienten in der
Studie eingeschlossen.
wurden mittels Durchflusszytometrie und
konfokaler Mikroskopie charakterisiert.
Eine funktionelle Charakterisierung
erfolgte in Gegenwart spezifischer αv Inhibitoren bezüglich ihres migratorischen
und invasiven Verhaltens. Neben der
Proteinexpression und Phosphorylierung
wurde auch Apoptose untersucht. Haptotaktische Stimulation durch Vitronektin
führte zu einer dosisabhängigen Zunahme der Zellmigration und konsekutiv
zu einer Zunahme der Phosphorylierung
von Tyrosin durch die focal adhesion
kinase (FAK). Dies konnte durch einen αv
-Inhibitor vollständig unterdrückt werden.
Zusätzlich unterbindet der αv -Inhibitor die
chemotaktische Migration. Die gesteigerte
Tyrosinkinasephosphorylierung im Bereich der glatten Muskelzellen konnte
mittels konfokaler Mikroskopie bestätigt
werden. Die in vitro – Invasion der hCASMC war in Gegenwart eines ±v Inhibitors
ebenfalls deutlich reduziert und ging mit
einer reduzierten Expression der Matrix –
Metalloproteinase 2 (MMP-2) einher. Dies
zeigt, dass eine ±v Inhibiton die Tyrosin –
Kinase Phosphorylierung an den Anheftungsstellen beeinflusst, vor allem
durch die FAK, und zusätzlich die Sekretion von MMP-2 verringert, was zu einer
verlangsamten Migration und Invasion der
hCASMC führt.
3.7 Clinic for Internal
Medicine I
3.7.2 Kontrollierte Migration der glatten
Muskelzellen mittels Beeinflussung der
Matrixproteine und Rezeptoren der Integrin – Familie:
3.7.1 Analysis of the impact of oral microbiological environment on the incidence
of myocardial infarction (MUNDART – trial):
Kooperation der Medizinischen Klinik mit
dem Zentrum für Infektionsforschung
Eine überschiessende Migration der
glatten Muskelzellen ist ein Schlüsselproblem bei der koronaren Restenose
nach Dilatation. Obwohl extrazelluläre
Matrixproteine und Rezeptoren der Integrin
– Familie eine bedeutende Rolle im
Prozess der Restenose darstellen, ist die
Regulation der Migration der glatten
Muskelzellen molekular noch nicht aufgeklärt. Primäre humane glatte Muskelzellen aus Koronararterien (hCASMC)
Recent investigations could demonstrate
a correlation between atherosclerosis,
coronary heart disease, myocardial
infarction and parodontitis. Patients
suffering from paradontitis have a 1.5 fold
higher risk for coronary heart disease, 2.2
fold higher risk for fatal myocardial
infarction and 2.8 fold higher risk underlying a stroke. The underlying biological
mechanisms are unclear. It is the aim of
the present study to investigate the impact
of the most parodontopathogen bacteria
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3. Die Institutionen des Zentrums für Infektionsforschung
(Actinobacillus actinomycetemcomitans
(Aa), Porphyromonas gingivalis (Pg),
Treponema denticola (Td), Bacteroides
forsythus (Bf), Eikenella corrodens (Ec)
and Spirochetes in patients suffering from
an acute myocardial infarction. Serological
and microbilological analysis will be
performed in patients with myocardial
infarction as well as in patients where a
coronary heart disease could be ruled out
by a coronary angiogramm. In this prospective, randomized, two center trial 160
patients from the university hospitals of
Würzburg and Münster will be included,
currently 89 patients are enrolled.
inhibitor abolished PDGF-BB-stimulated
chemotactic migration. CM confirmed the
increased tyrosine phosphorylation at VNinitiated focal contact sites in SMC, that
was reduced upon αv-inhibition. In vitro
invasion of hCASMC was severely compromised in the presence of the integrin
αv -inhibitor paralleled by decreased
levels of secreted matrix metalloprotease
2 (MMP-2). Therefore Integrin αv-inhibition
abrogates tyrosine phosphorylation at
focal adhesion sites, affecting in particular
FAK, and diminishes MMP-2 secretion
leading to reduced migration and invasion
of hCASMCs.
3.7.2 Controlling migration of smooth
muscle cells by modulation of matrix
proteins and receptors of the integrin
family:
Selected references:
- Nahrendorf M, Hu K, Frantz S, Jaffer
FA, Tung CH, Hiller KH, Voll S, Nordbeck P, Sosnovik D, Gattenlohner S,
Novikov M, Dickneite G, Reed GL,
Jakob P, Rosenzweig A, Bauer WR,
Weissleder R, Ertl G (2006) Factor XIII
deficiency causes cardiac rupture,
impairs wound healing, and aggravates
cardiac remodeling in mice with
myocardial infarction. Circulation.
113(9):1196-202.
- Kuhlencordt P, Hötten S, Schödel J,
Rützel S, Hu K, Widder J, Marx A,
Huang PL, Ertl G (2006) Atheroprotective effects of neuronal nitric
oxide synthase in apolipoprotein e
knockout mice. Arterioscler Thromb
VascBiol.26 (7):1539-44.
- Bauersachs J, Thum T, Frantz S, Ertl
G (2005) Cardiac regeneration by
progenitor cells—bedside before
bench? Eur J Clin Invest. 35(7):417-20
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Cooperation of the Medical Clinic and
Center for Infectious Diseases
Aberrant migration of smooth muscle cells
(SMC) is a key feature of restenosis.
Though extracellular matrix proteins and
their receptors of the integrin family play a
critical role in this process, their
contribution to cell migration in response
to different stimuli and their role in
regulating phenotypic changes required
for invasive motility of SMC is ill defined on
the molecular level. Primary human
coronary artery smooth muscle cells
(hCASMC) were characterized by flow
cytometry and confocal microscopy (CM).
They were functionally analysed in the
presence of a specific integrin ±v inhibitor
upon replating onto extracellular matrix
substrates and upon growth factor stimulation with regard to their migratory and
invasive potential. Protein expression and
phosphorylation were investigated by
Western Blot (WB) analysis and zymography, apoptosis was dentified by annexin-V staining. In hCASMC plated on
vitronectin (VN), αv-containing integrins
were localized at focal adhesion sites.
Haptotactic stimulation through VN led to
a dose-dependent increase in cell migration and concomitantly to enhanced
tyrosine phosphorylation of focal adhesion kinase (FAK). Both events were
completely blocked by an integrin αvinhibitor. Additionally, the integrin αv-
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3. Die Institutionen des Zentrums für Infektionsforschung
3.8 Medizinische Klinik und
Poliklinik II - Clinic for Internal
Medicine II
Hermann Einsele
10.01.1958
Professor Dr. med. Hermann Einsele
Medizinische Klinik und Poliklinik II
Klinikstraße 6-8
97070 Würzburg
Tel.: ++49 (0)9 31- 2 01 - 70000
Fax: ++49 (0)9 31- 2 01 - 70730
[email protected]
1977 – 1984
don
1984 – 87
1986
1988
1989 - 1996
1991
1992
1993
since 1993
since 1995
1996
since 1997
since 1999
since 1999
12/1999
12/2000
6/2000
7/2003
4/2004
Includes the following disciplines of
Internal Medicines:
Gastroenterology/Hepatology
-Hematology and Oncology
Rheumatology and Immunology
Psychosomatic medicine
Infectious diseases
A newly created centre of stem cell
transplantation has started its transplantation programme in March 2005.
Already in 2006 the stem cell transplantation programme (50 allogeneic/150
allogeneic stem cell transplantations) has
become one of the three largest in
Germany. Innovative techniques in stem
cell transplantation (cord blood transplantation, haploidentical stem cell transplantation) are performed. The large and
innovative stem cell transplantation programme also creates severe forms of
immunosuppression and thus a lot of infectious complications. Therefore together
with the section for Infectious diseases
(Head: Prof. Klinker) which concentrates
on HIV infection and different forms of
opportunities infections we have a large
patient population suffering from opportunistic infections. Thus several research
projects have been initiated to look at different forms of opportunistic infections (fungal
infections, CMV infections, EBV and respiratory virus infections, toxoplas-mosis).
This research is funded by two large grants
from the EU (EU FP 6 Allostem, EU FP6
Strep MANASP), the Deutsche Forschungsgemeinschaft (DFG SPP 1160: Analysis of
the interaction between Aspergillus fumigatus and human immune effector cells
and the induction of innate and adaptive
immune responses to this pathogen),
Eberhard-Karls-Universität Tübingen Lord Owens University Manchester Guy´s Hospital (Imperial College) Lon-
Research Fellow, Department of Haematology/Oncology/ Rheumatology/Immunology, University of Tübingen
MD Thesis: Membrane alterations of red bloods cells in liver disease (summa cum laude)
Fellow Max-Planck-Institute for Biochemistry, Martinsried
Member of the Research Network SFB 120 (Immunogenetics and Allo-SCT)
Board Certificate: Internal Medicine
Assistant Professor
Oberarzt
Member of ASH, EBMT, EBMT working parties Infectious Disease and Chronic Leukemia
Head of the Allogeneic Stem Cell Transplantation Programme
Board Certificate: Hematology/Oncology
Member of the SFB 510 (Stem cell transplantation and Antigen Processing)
Associate Professor
Chairman of the German Study Group Multiple Myeloma (DSMM)
Visiting Professor FHCRC, Seattle
Visiting Professor City of Hope Hospital, Duarte
Member of the Board of the German Society of Stem Cell Transplantation (DAG-KBT)
van Bekkum- Award European Society of Blood and Marrow Transplantation
Chairman of the Infectious Disease Working Party of the EBMT Board of the European Blood and Marrow Trans
plantation Society Member of the German Lymphoma NetWork
12/2004
Director of Medizinische Poliklinik Julius-Maximilians-University, Würzburg
Research Activities:
Immune reconstitution after Stem Cell Transplantation/GvHD (SFB 120 1988-1996), Local virus infections and associated
Cytokine Dysregulation in Autoimmune Diseases (BMBF 1988-1994), Herpes Virus Infections in Transplantation (BMBF 19932000), Molecular Diagnostics for Fungal Infection (Fortüne-Programme, Krebshilfe, since 1998 ), Adoptive T cell therapy after
Stem Cell Transplantation (SFB 510, since 1997), National Genome Network (TübinGenom) 2001- 2004, Genetic epidemiology
of invasive Aspergillosis, EU, FP6 Integreated Project: Allostem:Immunotherapy for CMV/EBV infection (start 02/2004), EU FP6
NoE Euronet-Leukemia „Supportive Care“ , Jose-Carreras-Foundation: Genetically modified T cells to combat Myeloma cells,
EU FP6 MANASP „Development of Novel Management strategies for invasive aspergillosis“, DFG: SPP 1160 since 2004
„Analysis of the interaction between ASpergillus fumigatus and human immune effector cells and the induction of innate and
adaptive immune responses to this pathogen“ , DFG: SFB 479 „Regulation der Herpesvirus-spezifischen T-Zell Immunität“, EU
FP 6 MANASP "Development of Novel Management strategies for invasive aspergillosis (start 01/2007).
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3. Institutions of the Research Center for Infectious Diseases
Deutsche Krebshilfe and also by several
industrial partners. In addition a new project
in the SFB 479 (Regulation der Herpesvirus-spezifischen T-Zell Immunität) has
been initiated looking at specific aspects
of HCMV infections. Further details of these
scientific projects are outlined below.
Clinical studies investigate the role of
adoptive T cell therapy and DC vaccination
for CMV, EBV and adenovirus infection and
invasive fungal infection.
Research Group has an international
reputation for performing immunotherapeutic studies for opportunistic infections.
Schwerpunkt Infektiologie
(Prof. Dr. H. Klinker)
Der Schwerpunkt „Klinische Infektiologie“
(Leiter: Prof. Dr. Klinker) der Medizinischen
Klinik und Poliklinik II der Universität befindet sich in Gebäude C6 und Gebäude D20
(wissenschaftliches Labor) am Standort
Luitpoldkrankenhaus.
.
Die Station „Schottmüller“ (20 Betten) ist
die Infektionsstation für Erwachsene des
Universitätsklinikums. Es werden dort Patienten mit einem breiten Spektrum infektiös bedingter Erkrankungen behandelt.
Schwerpunkte in Diagnostik und Therapie
stellen die AIDS-Erkrankung, akute und
chronische Virushepatitiden, Organtuberkulosen, Infektionen mit multresistenten Erregern, infektiöse Darerkrankungen
und opportunistische Infektionen unter
Immunsuppression bei Orgatransplantierten oder unter Chemotherapie dar.
Im Zeitraum 2005/2006 wurden ca. 1.700
Patienten stationär behandelt. Bereits seit
2002 wird klinikweit und für die Region ein
Konsiliardienst „Klinische Infektiologie“
angeboten.
Die Infektionsambulanz in Bau C6 verzeichnete im Zeitraum 2005/2006 rund
7.000 Patientenbesuche, 600 Patienten
wurden erstmals zugewiesen. Das Krankheitsspektrum umfasste vor allem die HIVInfektion und chronische Virushepatitiden.
Die Spezialambulanz zeichnet sich als
überregionales Zentrum durch eine hohe
Studienaktivität aus. So werden zahlreiche,
nationale und internationale klinische Studien insbesondere im Bereich der HIV-In-
ZINFbericht-final.P65
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fektion und der chronischen Virushepatitis
B und C durchgeführt. Darüber hinaus erfolgen in enger Kooperation mit dem
Schwerpunkt Hämatologie diverse Studien zur systemischen antimykotischen Therapie bei hämatologisch/onkologischen
Patienten (Dr. W. Heinz).
Der Schwerpunkt Infektiologie ist klinisches Zentrum in den vom Bundesministerium für Bildung und Forschung
(BMBF) geförderten Kompetenznetzwerken
„HIV/AIDS“ und „Hepatitis“. Im Jahre 2005
hat sich das Studienzentrum für das weltweite Studiennetzwerk für strategische HIVStudien „INSIGHT“ (International Network
for Strategic Initiatives in Global HIV Trials)
des National Institutes of Health/USA ( http:/
/www.insight-trials.org ) qualifiziert.
Im Leber-/Infektionslabor werden Spezialuntersuchungen zur quantitativen Leberfunktionsdiagnostik und zum Therapeutischen Drug Monitoring von Virustatika und
Antimykotika durchgeführt. Insgesamt erfolgten im Zeitraum 2005/2006 über 40.000
Messungen.
Der Schwerpunkt der Arbeiten liegt in Untersuchungen zur Pharmakokinetik von
HIV-Protease-Inhibitoren (PI) und Nicht
Nukleosidischen Reverse TranskriptaseInhibitoren (NNRTI) im Rahmen der Hochaktiven Antiretroviralen Therapie (HAART)
bei Patienten mit HIV-Infektion, daneben
wurde eine Plasmakonzentrationbestimmung von Azol-Antimykotika neu etabliert.
Im Jahre 2005 wurde der Schwerpunkt
Infektiologie von der Deutschen Gesellschaft für Infektiologie (DGI) als „Zentrum
Infektiologie (DGI)“ zertifiziert. Der Schwerpunktleiter hat neben der Bezeichnung
„Infektiologe (DGI)“ (2003) im Jahre 2005
die im Rahmen der aktualisierten Weiterbildungsordnung der Bayerischen Landesärztekammer neu geschaffene Zusatzweiterbildung „Infektiologie“ erworben und
erhielt im selben Jahr die volle Weiterbildungsbefugnis für diesen Bereich. Damit war der Schwerpunkt Infektiologie die
erste Einrichtung in Deutschland, in der die
gesamte Bandbreite der Qualifikationen im
Bereich der klinischen Infektiologie vorgehalten werden.
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3. Die Institutionen des Zentrums für Infektionsforschung
Division of Infectious Diseases
(Prof. Dr. H. Klinker)
The division of Infectious Diseases (head:
Prof. Dr. Klinker) of the Medizinische Klinik
und Poliklinik II, is located in building C6
and building D20 (scientific laboratory) of
the Luitpoldkrankenhaus.
Our ward, named by H. Schottmüller, is
caring for up to 20 patients and is equipped
for infectious diseases in adult patients. A
broad range of different infections is treated
there. Main focus in diagnostics and
therapy are HIV and AIDS, acute as well as
chronic viral hepatitis, tuberculosis and
infections with multiresistant bacterias.
Besides that, infectious diarrhea and
opportunistic infections in immuncompromised hosts, i.e. after chemotherapy or
organ transplantation are commonly seen.
In 2005/2006 a total of about 1.700
inpatients were treated on our ward. Already
in 2002 we started providing a consulting
service on clinical infectiology for the
university, and the clinicians and hospitals
in the region.
Our outpatient care unit had nearly 7.000
patient contacts in 2005/2006, 600 thereof
were seen for the first time. Regarding
these outpatients the clinical spectrum was
primarily focussed on HIV infection and
chronic viral hepatitis.
The outpatient clinic of infectious diseases
is known cross-community as a center
performing many clincal trials. Various national or international clincal trials are
performed especially concerning infection
with HIV and chronic hepatitis B or C,
Fig.1: HPLC illustration of ribavirin plasma concentration (+= Ribavirin 3.000 ng/
ml, Δ = Internal Standard (3-Methylcytidin-Methosulfat)
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respectively. In addition and in close
cooperation with the Department of Haematology, trials concerning invasive fungal
infections in haematologic or oncologic
patients are performed (Dr. W. Heinz).
The section of Infectious Diseases is a
clinical center of the „German Competence
Network on HIV/AIDS“ and the „German
Competence Network on Hepatitis“,
sponsored by the Bundesministerium für
Bildung und Forschung (BMBF). In the year
2005, the study-center qualified for the
worldwide study-network for strategical
HIV-studies „INSIGHT“ (International
Network for Strategic Initiatives in Global
HIV Trials) sponsored by the National Institutes of Health/USA (http://www.insighttrials.org).
Our laboratory is specialized in the development and implementation of methods
for an evaluation of quantitative liver function
and therapeutic drug monitoring of virostatic agents and antibiotics. In 2005/2006
over 40.000 analyses in this field could be
performed.
Main focus is the pharmacokinetic evaluation of HIV protease inhibitors (PI) and
non nucleoside reverse transcriptase
inhibitors (NNRTI) during highly active
antiretroviral therapy (HAART) in patients
with HIV-infection.
In 2005 the division of infectious diseases
was certified as „Zentrum Infektiologie
(DGI)“ (center of infectious diseases) from
the German Association of Infectiology
(DGI). After having already acquired the
certificate of specialisation in infectiology
(„Infektiologe DGI“) in 2003, the head of the
center also acquired the title of further professional training in infectiology con-ferred
from the Bavarian Medical Asso-ciation as
well as the license of further professional
education in the field of infectiology in 2005.
This center of infec-tious diseases was the
first one in Germany offering all
qualifications ac-quirable in clinical
infectiology.
High pressure liquid chromatographic
(HPLC) methods for determination of
plasma levels of HIV-1 Protease-Inhibitors
saquinavir, indinavir, ritonavir, nelfinavir,
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
amprenavir, lopinavir, atazanavir, and
tipranavir were developed in our laboratory
and evaluated for routine clinical use.
Current research aims at the long-term
efficacy especially of protease inhibitor
containing regimens. The main focus of
this research is the improvement of
protease inhibitor bioavailability by coadministration of small doses of ritonavir.
As a potent inhibitor of the major cytochrome
P450 drug-metabolizing enzyme CYP3A,
ritonavir substantially increases the bioavailability of other, co-administered
protease inhibitors. Thus, combination
protease inhibitor-therapy results in
increased plasma levels and in an increased half-life of the boosted PI. This
allows to reduce the dose and dosing
frequency of PIs. Especially to reduce the
dosing frequency often results in a better
patient‘s compliance.
It could be demonstrated that therapeutic
drug monitoring (TDM) of PI plasma
concentrations may prove useful in optimizing antiretroviral therapy. Multivariate
analysis showed PI plasma concentrations
to be an independent predictor of HIV-RNA
evolution.
Another HPLC method was developed for
77
the non-nucleoside reverse transcriptaseinhibitor efavirenz. Concentrations of
nevirapine, another NNRTI, were monitored by a gas chromatographic setup with
NP-detection during antiretroviral therapy
in patients with HIV infection.
Another topic of research was focussed on
the determination of nucleoside reverse
transcriptase inhibitors (NRTI) and investigations concerning the role of nucleoside
analogues in mitochondrial toxicity during
HAART .
NRTIs inhibit the synthesis of mitochondrial
DNA, are associated with cytotoxicity based
respiratory chain function disorders and
thus possibly also affect the de novo
synthesis of uridine. The intravenous or oral
supplementation of uridine has been
suggested to be of potential benefit in
improving the therapeutic index of some
cancer medication and also in abrogating
the mitochondrial toxicity of anti-HIV
nucleoside analogues.
It has been demonstrated in vitro and in
animal models that uridine may abrogate
such mitochondrial toxicity and possibly
even in humans. Uridine therefore is likely
a candidate for further clinical studies in
Hartwig Klinker
27.08.1955 in Bielefeld
Prof. Dr. med. Hartwig Klinker
Leiter des Schwerpunktes Infektiologie
Medizinische Klinik und Poliklinik II
Klinikum der Universität Würzburg
Josef Schneider-Str. 2
97080 Würzburg
Tel 0931/201-36020
Fax 0931/201-36022
[email protected]
www.medpoli.uni-wuerzburg.de/hepinf
1976 – 1982 studies in medicine at the University of Würzburg
1984 M. D., Julius-Maximilians-Universität Würzburg
Career history:
1982 – 1995 resident for internal medicine, Medizinische Universitätsklinik Würzburg, (head: Prof. Dr. K. Kochsiek)
1995 – 2000 senior physician, „Schwerpunkt“ of hepatology and infectious diseases, Medizinische Universitätsklinik, since
1998 Medizinische Poliklinik der Universität Würzburg (head: Prof. Dr. K. Wilms, since 2005: Prof. Dr. H. Einsele)
2000 – Head of the „Schwerpunkt“ of hepatology and infectious diseases, Medizinische Poliklinik der Universität Würzburg
Licensure/Certifications:
1982 Medical Licensure (Approbation als Arzt)
1989 Certificate for Internal medicine
1990 Certificate for gastroenterology
2002 Certificate for the field of infectious diseases (DGI)
2005 Certificate infectious diseases (BLÄK)
Academic Appointments:
1998 Habilitation for Internal medicine/Privatdozent (assistant professor), Julius-Maximilians-Universität Würzburg
2004 Apl. Professor, Julius-Maximilians-Universität Würzburg
Major Assignments:
since 1991 member of the Hygienekommisssion, Klinikum der Universität Würzburg
since 1992 member of the Arzneimittelkommission, Klinikum der Universität Würzburg
2001-2005 member of the Klinikumskonferenz, Klinikum der Universität Würzburg
Since 2005 member of the „Lenkungskreis HIV/AIDS in Western Cape/South Africa“ of the Bavarian Staatskanzlei
2006 member of the German hepatitis B therapy consensus group
2007 member of the scientific Board of the „3. Deutsch-Österreichischer AIDS-Kongress“
2007 member of the German HIV/AIDS therapy consensus group
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23.04.2007, 14:50
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3. Die Institutionen des Zentrums für Infektionsforschung
HIV-patients, aimed at alleviating the
mitochondrial toxicities of NRTIs.
For these studies, it is important to have
access to an analytical method which is
able to determine the uridine concentrations in HIV-patients without interfering
with the nucleosides in antiretroviral drug
combinations. In order to evaluate uridine
levels in humans a very sensitive and
specific high performance liquid chromatographic method for the determination of
uridine in serum was developed.
The standard of care in chronic hepatitis C
improved markedly and response rates
have multiplied in recent years. Treatment
options to achieve higher sustained
virological response rates not only in the
group of „difficult to treat patients“ remain a
challenge. Ribavirin (RBV) dose recommendations up to now are based on
body weight but RBV drug levels showed
high interindividual fluctuation. RBV drug
levels might play a crucial role not only in
correlation to treatment effectiveness, but
also in avoiding deteriorating drug addicted
side effects such as haemolytic anemia.
In this context individual therapy guidance
using therapeutic drug monitoring (TDM)
for RBV drug levels might play the crucial
role not only in correlation to treatment
effectiveness but also in deteriorating drug
addicted side effects such as haemolytic
anaemia in interferon-RBV combination
regimens might proof as a suitable tool.
Using high pressure liquid chromatographic equipment, we developed a
method for the detection of RBV (figure 1)
in blood which should be evaluated to
address the question whether standard
RBV dosing is inferior to RBV dose
adaptation guided by TDM. Another aims
of this investigation are to evaluate practicability of RBV treatment in patients with
HIV-hepatitis co-infection as well as
hepatitis C and terminal renal insufficiency
and to develop schemes for individualized
dose recommendations based on RBV
drug levels and correlate these findings
with viral kinetics, different genotypes and
be able to enhance and eventually predict
therapy response.
Invasive fungal infections (IFI) are a life
threatening complication in patients with
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78
haematological malignancies, especially
in those with acute myeloic leukemia or
who are undergoing allogenic stem cell
transplantation. These patients often
receive a number of different drugs for the
underlying disease, prophylaxis or treatment of complications like graft versus host
disease. Therefore, drug interactions are
a relevant problem in daily medical care.
Voriconazole and posaconazole are broadly used in treatment and in secondary
prophylaxis of IFI. Like all azole antimycotics, they are metabolized by CYP
P450-system and show inhibiting and as
well inducing activity for several isoenzymes
of CYP (2C9, 2C19 and 3A4). Only a few is
known about plasma concentrations (PC)
during multimedication. For further pharmacokinetic studies, new HPLC-based
methods were developed in our laboratory
and evaluated for clinical use in 2005-2006
(Dr. W. Heinz).
In addition to this scientific work in the
laboratory, numerous clinical studies on the
field of HIV-infection and chronic viral
hepatitis B and C were performed.
Studies to optimize the outcome of patients
with different genotypes or patients with a
relapse or breakthrough of their hepatitis
C were done with different combination
therapy regimens consisting of interferon,
ribavirin and amantadine. We participated
phase II and III studies to assess effectiveness and tolerance/side effects of
nucleoside analogues such as entecavir
and adefovir in chronic hepatitis B.
Concerning HIV, phase III studies on safety
and effectiveness of new HIV protease
inhibitors (tipranavir and darunavir) and a
CCR5 co-receptor inhibitor were conducted. Moreover, clinical studies were
started concerning the genetic background
of nevirapine- toxicity and abacavir-hypersensitivity.
For the last years we participated in the
NIH (National Institute of Health, Bethesda)
sponsored ESPRIT-study where long term
efficacy of a cyclic IL-2 (interleukin 2)
application on CD4 count in patients with
HIV is evaluated.
In 2004, the SMART-study was started by
the National Institute of Allergy and Infectious Diseases, Division of AIDS (NIAID) in
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
Bethesda. The purpose of this study is to
compare the long-term consequences of
two strategies of antiretroviral management: 1. a drug conservation strategy (DC),
aimed at conserving drugs through episodic use of antiretroviral treatment for the
minimum time to maintain CD4+ cell count
e“ 250 cells/µl, 2. the viral suppression
strategy (VS), a strategy aimed at suppressing viral load as much as possible,
immediately following randomization and
throughout follow-up, irrespective of CD4+
cell count. The section of infectious
diseases of the University of Würzburg is
one out of nine selected centers in Germany for this important study. Meanwhile,
enrolment into the study was stopped in
January 2006 when it was found that the
VS strategy was superior to the DC strategy
with regards to the primary endpoint
(Opportunistic Disease (OD)/death), allcause mortality, and serious adverse
events. The essential results of SMART
were published in November 2006 (N Engl
J Med 2006; 355: 2283-2296).
Clinical studies in patients with haematological malignancies mainly focus on
fungal infections. Due to different indications, underlying risk profiles and
timing of treatment, different compounds,
therapies and strategies are under investigation in phase I, II and II trials. In
patients with high risk of developing an
invasive fungal infection a new azole formulation is examined for primary prophylaxis.
The optimal timing for antifungal therapy in
this risk population is matter of continuing
discussion, new drugs including third
generation azoles and echinocandins as
well as lipid formulations of amphotericin
B allow earlier therapy with fewer side
effects. Here a national trial investigates
immediate versus deferred empirical
antifungal treatment. In the same study,
PCR for early diagnosis of invasive aspergillosis will be proven. As allogenic stem
cell transplantation and history of invasive
aspergillosis are both associated with a
clearly increased risk of invasive fungal
infection, long term secondary prophylaxis
is tested. Another trial looks for the safety,
tolerability and pharmacokinetic of an
echinocandin, a liposomal polyene or the
combination of both in stem cell transplant
patients. In addition, echinocandins are
ZINFbericht-final.P65
79
investigated for primary therapy or for the
second line treatment of invasive aspergillosis, as well as for the indication of
candidemia and invasive candidiasis. These clinical therapeutic trials are accompanied and assisted by diagnostic
research and surveys to the incidence of
fungal disease (Dr. W. Heinz).
More detailed informations on clinical
studies, main research projects and other
activities are shown on the website of the
division of infectious diseases.
(www.medpoli.uni-wuerzburg.de/hepinf)
Activities
- „Chronische Virushepatitis – Update
2005“, January 26, 2005, organized by the
Medical Clinic II (director: Prof. Dr. H.
Einsele), Division of Hepatology and
Infectious Diseases by Prof. Dr. Hartwig
Klinker and Priv. Doz. Dr. P. Langmann.
- „4. Würzburger Arzt-Patienten-Seminar:
Chronische Virushepatitis“, April 16, 2005,
organized by the Medical Clinic II, Division
Gastroenterology/Hepatology and Hepatology/Infectious Diseases by Prof. Dr. Michael Scheurlen and Prof. Dr. Hartwig Klinker.
- „Chronische Virushepatitis – Update
2006“, January 25, 2006, organized by the
Medical Clinic II, Division of Hepatology
and Infectious Diseases by Prof. Dr. Hartwig Klinker and Priv. Doz. Dr. P. Langmann.
- „Symposium 4. Würzburger Infektiologisches Symposium – Virushepatitis und
HIV-Erkrankung“, April 01, 2006, organized
by the Medical Clinic II, Division of Infectious
Diseases by Prof. Dr. Hartwig Klinker and
Priv. Doz. Dr. P. Langmann.
-„Management der HIV-Exposition in Geburtshilfe und Pädiatrie“, May 03, 2006, April
01, 2006, organized by the Medical Clinic
II, Division of Infectious Diseases by Prof.
Dr. Hartwig Klinker in cooperation with the
Universitäts-Kinderklinik (director: Prof. Dr.
C. P. Speer), Universitäts-Frauenklinik
(director: Prof. Dr. J. Dietl) and Missionsärztliche Klinik/Tropenmedizin (head: Priv.
Doz. Dr. A. Stich)
- „1. Würzburger Pilztagung“, July 12, 2006,
organized by the Medical Clinic II (director:
Prof. Dr. H. Einsele), Division of Infectious
Diseases by Dr. Werner Heinz
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3. Die Institutionen des Zentrums für Infektionsforschung
3.9 Neurologische Klinik und
Poliklinik und Institut für
Neurobiologie
Education in regular State Schools and at the University of Munich Medical School, Graduation 1970, postdoctoral education and MD thesis (Dr.med.) at the Munich Medical
School in Pediatrics and Pediatric Neurology; postdoctoral fellowship at the
Neuromuscular Division at Johns Hopkins Medical Institutions, Baltimore,MD (Dr. D.B.
Drachman) (1974 – 1976 ); further postdoctoral education in Neurology at the Technical
University of Munich Medical School (1976 – 1978), Lecturer (1978 –1979)
Klaus Toyka
Academic Posts: Associate (1979) and Full Professor (1981 -1989) at the University of
Düsseldorf Medical School, Vice-Chairman, Head, Division of Neuroimmunology.
Professor and Chairman at the University of Würzburg Medical School (1989 – present);
Dean, School of Medicine (1996 – 1998); Vice-Dean (1998 – 2002); Acting Dean (2002);
Assoc. Vice Dean (2005-present)
15. April 1945
Several awards and named lectureships, organizer and co-organizer of international
scientific meetings.
Member of academic boards and societies including honorary memberships in the
French, Belgian, and Polish Neurological Societies, in the Johns Hopkins Society of
Scholars, and in the Royal College of Physician, London (FRCP by distinction); President
of the European Neurological Society (2001 – 2002);
Advisor and Consultant to several research organizations and to the pharmaceutical
industry; board member on international advisory boards (Schering, Serono, Biogen
Idec, Sanofi-Aventis, Teva, Medac)
Scientific publications: author and co-author of over 390 original publications with an
emphasis on pathogenesis and treatment of neuromuscular disorders, multiple sclerosis,
and immune mediated disorders including experimental studies using animal models
of human diseases; author and contributor to books and book chapters, review articles in
national and international periodicals.
Prof. Dr. Klaus V. Toyka, M.D., FRCP
Neurologische Klinik der
UniversitŠt WŸrzburg
Josef Schneider Strasse 11
97080 WŸrzburg
Tel.: ++49 (0)9 31 2 01-2 37 51
Fax: ++49 (0)9 31 2 01-2 39 46
[email protected]
ZINFbericht-final.P65
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A number of excellent scholars of the past 20 years have contributed to the scientific
productivity of the former Division of Neuroimmunology at Düsseldorf and of the Würzburg Department. Many of them have made a carrier as chairmen in Neurology and/or in
the Neurosciences including Reinhard Hohlfeld (Munich), Hans-Peter Hartung (Düsseldorf), Heinz Reichmann (Dresden), Martin Koltzenburg (London,UK), Michael Sendtner
(Würzburg), Georg Becker (Homburg), Ralf Gold (Bochum), Peter Rieckmann (Canada,
in preparation).
Hobbies: Classical music education in violin, emphasis on chamber music; mountain
sports, cuisine with a personal cookbook co-authored by his wife Regine (4 editions in
German and 2 in English, first edition in Italian).
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
3.9 Department of Neurology
and Institute of Neurobiology
gag was absent in unstimulated human cerebral
endothelial cell cultures, however, it became
detectable after infection of cerebral endothelial
Project: Expression of human endogenous
retrovirus (HERV)-W in human cerebral
endothelial cells and its role in the
pathogenesis of MS
Dr. Klemens Ruprecht (1,2),
Dr. Jürgen Schneider-Schaulis (3),
Dr. Karola Obojes (1,3),
Dr. Herve Perron (4),
Prof. Peter Rieckmann (1)
1) Department of Neurology, Clinical
research unit for multiple sclerosis and
neuroimmunology
2) Department of Virology, University of
Saarland, Homburg
3) Department of Virology and Immunobiology,
4) bioMerieux, R&D, Marcy L’Etoile, France
Multiple sclerosis (MS) is a frequently
disabling inflammatory disease of the
central nervous system which is thought
to arise from a complex interplay between
genetic and environmental factors. Among
environmental factors, (retro)viruses have
repeatedly been involved in the pathogenesis of MS, although none of the
agents implcated so far has been shown
to play a unique causative role in this
disease. The multiple sclerosis - associated retroviral element (MSRV) is a
retroviral particle previously identified in cell
culture supernatants from patients with
MS. Interestingly, MSRV has genetically
homologous endogenous counterparts in
human DNA, the human endogenous
retrovirus family type W (HERV-W).
We have recently demonstrated prominent expression of the MSRV/HERV-W gag
protein in brain endothelial cells of acute
or actively demyelinating chronic MS
lesions, a pattern not found in normal
controls.
cells with herpes simplex virus type-1 (HSV1). The transactivation of HERV-W proteins by
HSV-1 could enhance their potential oligodendrotoxic and immunopathogenic effects,
representing a mechanism
by which HSV-1, and possibly also other herpes
viruses associated, could be linked to the
pathogenesis of this disease.
Currently, cellular and humoral immune reactions
against HERV-W gag protein are being
investigated in MS patients and healthy controls.
Project: Anti EBV-specific, HLA-restricted
T cells and their role in the pathogenesis of
multiple sclerosis
Dr. Felix Gronen (1),
Dr. Klemens Ruprecht (1,2),
Dr. Benedikt Weissbrich (3),
Dr. Erdwine Klinker (4),
Dr. Harald H. Hofstetter (1),
Prof. Peter Rieckmann (1)
1) Department of Neurology, Clinical
Research Unit for Multiple Sclerosis and
Neuroimmunology
2) Department of Virology, University of
Saarland, Homburg
3) Department of Virology and Immunobiology
4) Department for Transfusion Medicine
and Immunohematology
The Epstein-Barr virus (EBV) has been
implicated in the pathogenesis of multiple
sclerosis (MS), however, the mechanisms by
which EBV may be involved in MS are unknown.
We here have investigated the frequency of
EBV-specific cytotoxic T lymphocytes (CTL) in
human leukocyte antigen (HLA)-B7+ patients
with MS and healthy controls using enzymelinked immunospot assays and seven previously
characterized HLA-B7-restricted immunogenic
As retroviruses contain regulatory elements,
EBV peptides. Overall, there were no significant
which can by transactivated by other virus
differences in the frequency of EBV-specific
infections, we set up an in vitro model of cultured
CTL between both groups. These data do not
human cerebral endothelial cells to examine
support the hypothesis that EBV could play a
regulation and possible transactivation of HERV-
role in MS by inducing EBV-specific CTL
W gag by common viruses in this important
responses in a quantitative manner. Other
element of the blood brain barrier. In keeping
pathogenic mechanisms involving EBV in the
with the neuropathological findings, HERV-W
pathogenesis of MS remain to be elucidated.
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3. Die Institutionen des Zentrums für Infektionsforschung
Project: Molecular mechanisms of interferon-β mediated antiviral defense
Dr. Mathias Buttmann (1),
Dr. Friederike Berberich-Siebelt (2),
Prof. Edgar Serfling (2),
Prof. Peter Rieckmann (1)
1) Department of Neurology, Clinical Research Unit for Multiple Sclerosis and
Neuroimmunology
2) Department of Pathology, Section for
Molecular Pathology
Most virus-infected cells release interferonβ (IFN-β) as a powerful inducer of antiviral
defence. Endothelial cells tightly regulate
local immune cell recruitment by expression of adhesion molecules and
chemokines. Here, we studied the transcriptional regulation of IFN-β-induced
chemokine expression in primary human
endothelial cells. IFN-β increased monocyte chemoattractant protein-1/CCL2
moderately and raised IFN-γ-inducible
protein-10/CXCL10 mRNA steady-state
levels and protein release strongly, while
no effect was detected on various other
chemokines. As shown by transient transfections, induction of CXCL10 expression
depends on an IFN-stimulated response
element (ISRE) within
the CXCL10 promoter. A double point
mutation of the putative IFN regulatory factor
(IRF)-1/2 binding site within this ISRE motif
abolished IFN-β-induced promoter activity.
In electrophoretic mobility shift assays, this
ISRE motif showed a basal IRF-2 and an
IFN-β-inducible IRF-1 and augmented IRF2 binding. Furthermore, stimulation with
IFN-β induced a rapid nuclear translocation of signal transducer and activator
of transcription 1 (STAT1) and STAT2 and
their transient binding to a g-activated site
within the CCL2 promoter. The kinetics of
transient STAT1 binding to this -activated
site element correlated with the amount of
Y701-phosphorylated nuclear STAT1, while
S727-phosphorylated nuclear STAT1 remained stable over 24 h after stimulation.
Therefore, IFN-β potently induces endothelial chemokine expression at the transcriptional level.
ZINFbericht-final.P65
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Selected References:
- Perron H,, Lazarini F, Ruprecht K, P•chouxLongin C, Seilhean D, Sazdovitch V, Cr•ange
A, Battail-Poirot N, Sibai G, Santoro L, Jolivet
M, Darlix JL, Rieckmann P, Arzberger T, Hauw
JJ, Lassmann H. (2005) Human endogenous
retrovirus (HERV)-W env and gag proteins:
physiological expression in human brain and
physiopathological modulation in multiple
sclerosis lesions. J. Neurovirol. 11: 23-33.
- Kroner A, Rosche B, Kolb-MŠurer A, Kruse
N, Toyka KV, Hemmer B, Rieckmann P, MŠurer
M. (2005) Impact of the Asp299Gly polymorphism in the toll-like receptor 4 (tlr-4) gene
on disease course of multiple sclerosis. J.
Neuroimmunol. 165: 161-5.
- Ruprecht K, Obojes K, Wengel V, Gronen F,
Kim KS, Perron H, Schneider-Schaulies J,
Rieckmann P.(2006) Regulation of human
endogenous retrovirus-W protein expression
by herpes simplex virus type 1: Implications
for the pathogenesis of multiple sclerosis. J.
Neurovirol. 12; 65-72.
- Gronen F, Ruprecht K, Weissbrich B, Klinker
E, Hofstetter H, Kroner A, Rieckmann P. (2006)
Frequency of HLA-B7-restricted Epstein -Barr
virus-specific cytotoxic T lymphocytes in
patients with multiple sclerosis. J. Neuro
immunol. 180: 185-192
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
Education and medical training:
1981-1982 „Studium generale“ at the University of Hamburg
1982-1988 Medical school at the Georg-August-Universität Göttingen
1988
Medical thesis: „Immunglobulin-producing cells in the cerebrospinal fluid“
(summa cum laude)
1995
Board certification: Neurology
1995
Habilitation thesis: Cytokine and adhesion molecules: activity parameters
andtargets for immunomodulatory therapy of multiple sclerosis
Chronology of clinical and academic positions:
1988-1989 Training in Neurology, Department of Neurology, University of Göttingen
(Prof. Felgenhauer)
1989-1991 Post-doc-fellowship: Laboratory of Immunoregulation,
National Institute of Allergy and
Infectious Diseases, NIH, Bethesda, Maryland, USA (Dr. A.S. Fauci)
1991-1995 Training in Neurology,Clinical Neurophysiology and Psychiatry at
Department of Neurology, University of Göttingen (Prof. Felgenhauer)
1992-1995 Research group leader: Immunomodulation in the central nervous system,
Department of Neurology, University of Göttingen (Prof. Felgenhauer)
since 1996 Consultant and lecturer in Neurology, Department of Neurology,
Univ. Würzburg (Prof. Toyka)
since 1997 Research group leader: Clinical research unit for Multiple sclerosis
and neuroimmunology
1992-1997 Gerhard-Hess-fellowship (German Research Association)
since 2001 Associate Professor for Neurology
Awards:
1994
Langheinrich-Prize for Multiple-Sclerosis-Research
1996
KŠte-Hammersen-Prize (German Multiple Sclerosis Society)
1996
Award of the medical faculty (University Gšttingen) for the best Habilitation
thesis
1999
Hans-Heinrich-Queckenstedt-Prize
2000
Wartenberg-Lecture (German Neurological Association)
Scientific publication:
Over 150 original publication mainly on aspects of multiple sclerosis and blood brain
barrier
Membership in professional boards:
Ethics Committee of the Medical Faculty, University of Würzburg
European Committee for Trials and Research in MS (ECTRIMS)
Medical Advisory Board of the MSIF
Medical Advisory Board of the German MS Society (DMSG)
Vice president of the Executive Board DMSG
Steering committees and advisory boards of various international multi-center clinical
trials
Co-Chairman of the International Multiple Sclerosis Therapy Consensus Group
(MSTCG)
Steering committees and advisory boards of various international multi-center clinical
trials
Co-Chairman of the International Multiple Sclerosis Therapy Consensus Group (MSTCG)
83
Peter Rieckmann
23. Mai 1961
Prof. Dr. Peter Rieckmann
Neurologische Klinik der
Universität Würzburg
Josef Schneider Strasse 11
97080 Würzburg
Tel.: ++49 (0)9 31 2 01-2 37 51
Fax: ++49 (0)9 31 2 01-2 3697
[email protected]
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3. Die Institutionen des Zentrums für Infektionsforschung
3. 10 Universitäts-Kinderklinik
Pädiatrische Infektiologie
Interaktion von Borrelia burgdorferi, dem
Erreger der Lyme Borreliose, mit humanen synovialen Zellen (AG PD Dr. H.
Girschick, Dr. K. Latsch. Dr. S.K Singh, S.
Singh)
Die Lyme Arthritis ist durch eine starke entzündliche Reaktion vermutlich wegen des
Vorhandenseins von Borrelia burgdorferi
in dem betroffenen Gelenk gekennzeichnet. Es wird vermutet, dass der Erreger direkt eine Rolle in dem entzündlichen Geschehen spielt. Proinflammatorische
Effektorzellen des Immunsystems, wie
Leukozyten und Lymphozyten wandern in
das Synovialgewebe durch das Gefäßendothelium ein. In vielen Fällen sammeln
sich die rekrutierten Lymphozyten in der
entzündeten Synovia und bilden Lymphfollikel, auch Keimzentren genannt. Leukozyten, Fibroblasten und andere Zellen im
Christian P. Speer
28. August 1952
Prof. Dr. Christian P. Speer, FRCPE
Direktor der Univ.-Kinderklinik
Josef-Schneider-Straße 2
97080 Würzburg
Tel.: ++49 (0)931 -201-27830
Fax: ++49 (0)931 - 201 27833
[email protected]
ZINFbericht-final.P65
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Synovialgewebe produzieren verschiedene entzündliche Botenstoffe. Die Produktion dieser proinflammatorischen Faktoren
durch Synovialzellen als Reaktion auf das
Vorhandensein von B. burgdorferi könnte
zu den typischen Symptomen von Arthritis
wie z.B. den Ergüssen beitragen (Singh
and Girschick, 2004b) (Singh and Girschick, 2004a). Bis jetzt sind die Anfänge
der Entzündung bei der Lyme Arthritis jedoch nicht im Detail untersucht worden. Es
ist nicht bekannt, ob eine direkte Interaktion von B. burgdorferi mit Synovialzellen ein
entscheidender erster Schritt für die beschriebene Kaskade von Entzündungsvorgängen sein kann. Auf der Basis dieser
Überlegungen wurden weiterführende Experimente entworfen, in welchen Synovialzellen in der Zellkultur mit B. burgdorferi
Isolaten Geho und B31 exponiert wurden.
Wie bereits im Vorbericht ausgeführt haben wir mittels semiquantitativer RT-PCR
die relative Chemokin mRNA Expression
einer Vielzahl von Chemokinen, welche in
Academic career:
1971-1977 Medical School, Georg-August-University Göttingen
1976-1977 Practical Year, Department of Surgery, Internal Medicine and Department
of Pediatrics, University of Göttingen
1977
Examen and Doctoral Thesis
1978-1986 Resident, Dept. of Pediatrics, University of Göttingen: General Pediatrics,
Oncology, Endocrinology, Neuro-pediatrics, Intensive care, Neonatology
1982 -1983 Research Fellow: National Jewish Hospital and Research Center,
Dept. of Pediatrics, Denver, Co., USA, Research grant from „Deutsche
Forschungsgemeinschaft“
1986
Thesis (Venia legendi), University of Göttingen
Function in Societeies and Awards:
1987
Appointment as Associate Professor of Pediatrics, University of Göttingen
1993 – 1996 Secretary of the „European Working Group of Neonatology“, European
Society of Pediatric Research
1994
Professor of Pediatrics, Director of the Department of Neonatology,
University Children’s Hospital Tübingen
Since 1994 Editor – „Zeitschrift für Geburtshilfe und Neonatologie“
1996
Appointment as „Fellow of the Royal College of Physicians“, Edinburgh
1999
Professor of Pediatrics, Director of the University Children’s Hospital Würzburg
1999 – 2004 Executive Board of the European Association of Perinatal Medicine
2000 – 2004 Peer Reviewer for Pediatrics, Deutsche Forschungs-gemeinschaft
Since 2004 Editor in Chief „Biology of the Neonate“
2004
Appointment to the „Geoffrey-Thorburn Visiting Professor“ of the „Perinatal
Society of Australia and New Zealand“
2005
Invitation by the Hong Kong Pediatric Society to give the „James Hutchison’s
Memorial Lecture 2005".
2006
„Chiesi Award for Excellency in Neonatology 2006“ of the European
Association of Perinatal Medicine
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
menschlichen Synovialzellen nach Exposition/Infektion mit Borrelia burgdorferiIsolaten produziert werden, in vitro bestimmt. Dies erfolgte mittels Immunosorbant Assay (ELISA). Diese Ergebnisse
sind mittlerweile publiziert und zeigen, dass
ein „Orchester“ von Chemokinen eine wichtige Rolle in der Immunpathogenese von
früher Lyme-Arthritis spielen können, insbesondere konnten wir zeigen, dass die
Chemokine MCP-2 in Ihrer Genexprression
ebenso wie MIP-1α induziert werden. Allerdings war die letztendliche Chemokinkonzentration im Überstand supprimiert, was auf einen verstärkten RNA-Abbau hindeutet. Wir konnten zeigen, dass
das Chemokin SDF-1 ein konstitutionell
exprimiertes Chemokin ist und dass dieses vor und nach Infektion mit Borrelia
burgdorferi in Synovialzellen konstant auf
Proteinebene exprimiert wird (Singh et al.,
2005). Bereits früher konnten wir zeigen,
dass Metalloproteinasen und Cyclooxygenasen in Synovialzellen verstärkt
exprimiert werden und hier v. a. die
Metalloproteinase 1 (Singh et al., 2004).
Diese direkte proinflammatorische Reaktion, welche auch mit einer Induktion von
Cyclooxygenasen (COX-2) und entsprechender Postaglandin-Produktion einherging, haben wir mittlerweile in der Literatur
berichtet (Singh et al., 2004). Da bisher
nicht klar war wie die komplexe Interaktion
von Borrelia burgdorferi mit dem menschlichen Wirt auf molekularer Ebene abläuft,
erschien es nahe liegend, dass ins-besondere das sog. Toll-like-Rezeptor-System
eine entscheidende Rolle spielen könnte.
Hier ist anzumerken, dass gerade der Tolllike-Rezeptor 2 durch die Erkennung von
Lipoproteinen ein wichtiger primärer Rezeptor für die Erkennung von Borrelia
burgdorferi sein könnte. Borrelia burgdorferi exprimiert keine Lipopolysaccharide
auf seiner Oberfläche, dafür aber eine Vielzahl von Lipoproteinen. Gerade letztere
werden von Toll-like-Rezeptor 2 in Verbindung mit Toll-like-Rezeptor 1 möglicherweise erkannt. Ein weiteres Molekül was
erkannt werden kann, ist das Geisel-Antigen durch den Toll-like-Rezeptor 5. Um
hier Studien vorzubereiten haben wir eine
Übersichtsarbeit zu diesem Thema geschrieben (Singh and Girschick, 2006) und
Frau Dr. Latsch hat bereits erste Ergebnis-
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85
se zur Toll-like-Rezeptor-Interaktion von
menschlichen Synovialzellen mit Burgdorferi erarbeiten können. Hier zeigte sich,
dass die Oberflächenproteine C-defizienten Stämme B31 und Geho ein sehr
geringes Stimulationspotential gegenüber
den Synovialzellen aufweisen. Durch den
Einsatz von rekombinantem, lipidiertem
Oberflächenprotein A und C konnte sie jedoch erstmals zeigen, dass gerade
Synovialzellen, welche von LymearthritisPatienten isoliert worden waren, be-sonders empfindlich auf die Exposition mit
OSP C reagierten. Hier konnte sie eine bis
zu 200-fach erhöhte Genexpression von
Toll-like-Rezeptor-2 nachweisen, welche in
der Kontrolle und in der OSP A-exponierten Gruppe nicht nachweisbar war. Diese
Arbeiten wurden auf dem diesjährigen
Kinderärztekongress der Deutschen Gesellschaft für Kinderheilkunde und Jugendmedizin mit dem 1. Posterpreis ausgezeichnet. Somit scheint sich abzuzeichnen,
dass die komplexen Regulationsvorgänge
auf der Ebene von Chemokinen, Zelladhäsionsmolekülen (Singh et al., 2006),
Metalloproteinasen und Cyclooxygenasen
in der Interaktion mit Toll-like-Rezeptor-2
ihren molekularen Ursprung haben.
Ein weiteres Feld in der Arbeitsgruppe Priv.Doz. Dr. H. Girschick ist die Evaluation chronisch-nicht bakterieller Osteomyelitiden im
Kindesalter in welchem Rahmen wir unsere Langzeitverlaufsergebnisse nun berichten konnten (Girschick et al., 2005). Die
Erkrankung Hypophophatasie ist bereits
seit Jahren ein klinischer Schwerpunkt von
PD Dr. Girschick. Hier konnte nun in Zusammenarbeit mit dem Institut für Hygiene und Mikrobiologie die molekulare Analyse des Biofilms von Zähnen der betroffenen Kinder berichtet werden. Kindern mit
Hypophosphatasie fallen die Zähne vorzeitig aus, so dass die Frage bestand, in wie
weit ein besonders aggressives Keimgemisch bestehen könnte. Wir konnten
jedoch zeigen, dass der Biofilm vergleichbar ist mit einer gesunden Population
(Valenza et al., 2006). Interessante Fallberichte zu infektiologischen Themen wurden im Berichtszeitraum erstellt (Kunzmann et al., 2005) (Klotz et al., 2006).
23.04.2007, 14:50
Hermann Girschick
Univ.-Kinderklinik
Josef-Schneider-Straße 2
97080 Würzburg
Tel.: 0931 / 201-27830
Fax: 0931 / 201 27833
[email protected]
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3. Die Institutionen des Zentrums für Infektionsforschung
Modifizierung pulmonaler remodelling Prozesse durch pränatale Infektionen
(AG Prof. Dr. C. P. Speer, PD Dr. B. W.
Kramer, Dr. S. Kunzmann)
Die bonchopulmonale Dysplasie (BPD)
des Frühgeborenen ist durch eine Störung
der normalen Lungenalveolisation und vaskulation charakterisiert. Transforming
growth factor beta (TGF-β) spielt dabei sowohl eine wichtige Rolle in der normalen
Lungenentwicklung und der pulmonalen
Inflammationsregulation, als auch bei pulmonalen remodelling-Prozessen. Connective tissue growth factor (CTGF) fungiert
hierbei als downstream Mediator von
TGF-β und beeinflusst die Integrität und
Stabilität der extrazellulären Matrix. Zusätzlich födert CTGF die Angiogenese und das
vascular remodelling. In einem Tiermodel
für Chorioamnionitis sollte die Regulation
von TGF-β und CTGF in der Lunge untersucht werden. Chorioamnionitis ist mit
Frühgeburtlichkeit und Veränderung der
Lungenarchitektur und der Lungengefäße
assoziiert, die vergleichbar mit denen bei
der BPD von Frühgeborenen sind.
Hierfür wurden die Lunge von frühgeborenen Schafe mit einem Gestationsalter
von 125 Tagen 5 h, 24 h, 72 h und 7 Tage
nach Endotoxin-Injektion (4 mg) in das
Fruchtwasser auf die Expression von
TGF-β und CTGF mittels RT-PCR auf mRNA
und mittels Western Blot und Immunhistochemie auf Protein hin untersucht.
Eine Aktivierung des durch TGF-b induzierten Smad-Signaltransduktionsweges
in der Lunge wurde durch den spezifischen
immunhistochemischen Nachweis von
phosphorylierten Smad2 untersucht.
Für TGF-β zeigte sich im Vergleich zur
Kontrollgruppe eine zeitabhängige Zunahme der Expression sowohl für mRNA, als
auch für Protein. Parallel dazu konnte auch
eine Phosphorylierung des Signaltransduktionsproteins Smad2 und somit eine
Aktivierung des Smad-Signaltransduktionsweges im Lungengewebe festgestellt
werden. Für CTGF zeigte sich immunhistochemisch eine spezifische Expression in Lungenendothelzellen. In diesen
wurden 7 d nach Endotoxin-Applikation
CTGF deutlich vermindert exprimiert. Diese Verminderung von CTGF konnte auch
auf mRNA Ebene bestätigt werden. Zu-
ZINFbericht-final.P65
86
sätzlich zeigte sich eine Erhöhung des
proinflammatorischen Zytokins TNF-α in
der Lunge.
Chorioamnionitis führt zu einer systemischen und lokalen, pulmonalen Entzündungsreaktion. Dabei wird TGF-β1 vermehrt in der Lunge synthetisiert. Dies führt
zum einen zu einer Inhibition der normalen Lungenalveolarisation, zum anderen zu
einer Suppression der Entzündungsreaktion in der Lunge. Daneben wirkt
TGF-β1 auf die Wundheilungsprozesse im
Lungenbindegewebe (airway remodelling),
was bei repetitive Schädigung zu fibro-tischen Umbauprozessen in der Lunge führen kann. Das gleichzeitig erhöhte
TNF-β in der Lunge verhindert die Induktion von CTGF durch TGF-β1. Hierdurch wird
zum einen der physiologische Heilungsprozess im Lungenbindegewebe gestört,
zum anderen jedoch auch das Ausmaß der
fibrotische Umbauprozess in Lunge vermindert, was typisch für die histologische
Form der BPD ist. Zum anderen könnte die
Herunterregulation von CTGF die normale
Lungenendothelzell-Funktion, sowie die
Entwicklung und die Regeneration von
Endothelzellen beeinflussen.
3.10 Children Hospital Paedriatic Infectiology
Interaction of Borrelia burgdorferi, the Lyme
disease spirochete, with human synovial
cells (AG PD Dr. H. Girschick Dr. K. Latsch.
Dr. S.K Singh, S. Singh)
Lyme arthritis is characterized by a strong
inflammation in the affected joint. There are
reports that the Lyme disease spirochete
Borrelia burgdorferi is present in the joints
and is contributing directly to the inflammation. Proinflammatory cellular
components of the immune system are
being recruted to the joint. Lymphocytes are
forming lympoid follicles or germinal
centers. Leukocytes and fibroblasts located in the joint are producing a variety of
molecules involved in chemotaxis (chemokines), adhesion (cell adhesion molecules
CAMs), tissue destruction (matrix metalloproteinases MMP), and pain and in-
23.04.2007, 14:50
3. Institutions of the Research Center for Infectious Diseases
flammation (cyclooxigenases COXs).
Synovial cells are specialized fibroblasts
capable of producing the just mentioned
molecules. Synovial cell activation could
contribute significantly to the inflammatory
reaction. In a coculture system using
Borrelia burgdorferi together with synovial
cells we could demonstrate, that the
chemokine MCP-2 in addition to MIP-1β
was strongly induced regarding the gene
expression, however, the chemokine
concentration in the supernatant was
suppressed. This suggested a high RNA
degradation in those activated synovial
cells. In addition, the chemokine SDF-1
was constitutively expressed. As we have
shown before the expression of MMP-1
was induced in synovial cells exposed to
Borrelia burgdorferi. In addition, COX-2
gene expression was also induced. So far,
it was not clear how this complex interaction
of Borrelia burgdorferi and the human host
is determined on molecular level. We were
considering the Toll-like-receptor system
to play a role since it is known that Toll-likereceptor 2 is a major receptor for lipoproteins expressed by Borrelia burgdorferi.
This bacteria does not express lipopolysaccharides therefore lipoproteins are
the targets of interaction. We have gathered
preliminary results showing that the outersurface protein (OSP) C is able to significantly stimulate synovial cells resulting in
a tremendous 200-fold elevation of the gene
expression of toll-like-receptor 2. This effect
was not seen with recombinant OSP A.
Using Borrelia burgdorferi strains expressing OSP C in low or non-existing
amounts we also could show that no
stimulation of toll-like-receptor 2 mRNA
resulted after exposure. Thus, we will
conduct further experiments with genetically altered borrelia strains or human
isolates expressing OSP C in a significant
amount. Our results demonstrated a
complex interaction of Borrelia burgdorferi
with human synovial cells. The differential
expression of chemokines, MMPs, COXs
and especially Toll-like receptors in synovial
cells could be essential triggers in the
generation of Lyme arthritis.
In addition to this basic science project,
the group of H. Girschick also worked on
the evaluation of chronic non-bacterial
osteomyelitis in childhood in addition to the
ZINFbericht-final.P65
87
bacterial colonization of the oral cavity in
hypophosphatasia patients. A few clinical
case reports have been published
regarding rare aspects of infectious
diseases.
Antenatal inflammation induced TGF-β1
but suppressed CTGF in preterm lungs
(AG Prof. Dr. C. P. Speer, PD Dr. B. Kramer,
Dr. S. Kunzmann)
Chorioamnionitis is frequently associated
with preterm birth and increases the risk of
adverse outcomes such as bronchopulmonary dysplasia (BPD). Transforming
growth factor (TGF)-β1 is a key regulator of
lung development, airway remodelling, lung
fibrosis and regulation of inflammation,
and all these processes contribute to the
development of BPD. Connective tissue
growth factor (CTGF) is a down-stream
mediator of some of the pro-fibrotic effects
of TGF-β1, of vascular remodelling and of
angiogenesis. TGF-β1 induced CTGF
expression can be blocked by tumor
necrosis factor (TNF)-β. We asked if
chorioamnionitis associated antenatal
inflammation would regulate TGF-β1, the
TGF-β1 signalling pathway and CTGF in
preterm lamb lungs. Fetal sheep were
exposed to 4 mg intra-amniotic endotoxin
or saline for 5 h, 24 h, 72 h or 7 days before
preterm delivery at 125 days gestation age
(term is 150 days). Intra-amniotic endotoxin
increased lung TGF-β1 mRNA and protein
expression. Elevated TGF-β1 levels were
associated with a TGF-β1-induced phosphorylation of Smad2. CTGF was selectively expressed in lung endothelial cells
in control lungs and intra-amniotic endotoxin caused CTGF expression to decrease
to 30% of control values and
TNF-β protein to increase. The antenatal
inflammation induced TGF-β1 expression
and Smad signalling in the fetal lamb lung
may contribute to impaired lung alveolarization and to reduced lung inflammation.
Decreased CTGF expression may inhibit
vascular development or remodelling and
limit lung fibrosis during remodelling. These effects may contribute to the impaired
alveolar and pulmonary vascular development that is the hallmark of the histologic
form of BPD.
23.04.2007, 14:50
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3. Die Institutionen des Zentrums für Infektionsforschung
3.11 Klinik und Poliklinik für
Haut- und Geschlechtskrankheiten
3.11 Department of Skin Diseases and Veneral Diseases
Zusammenfassung
Summary
Zur Auslösung einer spezifischen Immunantwort gegen Mikroorganismen sind dendritische Zellen (DZ) als Bindeglied zwischen angeborener und erworbener Immunität von grundlegender Bedeutung. Die
Auseinandersetzung der DZ mit Pathogenen bestimmt maßgeblich den weiteren
Verlauf einer Infektion. DZ sind in der Lage,
zwischen verschiedenen Mikroorganismen zu unterscheiden und eine maßgeschneiderte antimikrobielle Immunantwort
zu initiieren. Auf der anderen Seite können
Pathogene jedoch auch mit der Funktion
dendritischer Zellen interferieren und damit ihre Elimination verzögern oder verhindern. Untersuchungen humaner DZ und
ihrer Vorläuferzellen in der Interaktion mit
unterschiedlichen intra- und extrazellulären Pathogenen können grundlegende
Einblicke in die Pathogenese geben.
To resist microbial infection, the host has
developed plenty of defence mechanisms
of the innate and adaptive immune system.
Dendritic cells (DCs) provide the link
between these arms of immunity. The
initiation of an immune response is
critically dependent on the activation of
these cells. DCs can discriminate between
different classes of microorganisms and
elicit tailored antimicrobial immune responses. They have an extraordinary
capacity to stimulate naïve
T cells and initiate primary immune responses. In turn, some pathogens interfere
with DC function to block or delay their
elimination by the host. Progress in
understanding the role of DCs in the
response to microbes discloses pathogenesis of microorganisms.
Eva-B. Bröcker
Projects:
1. Juni 1946
The reported projects were performed in
cooperation with Prof. M. Frosch / Dr. O.
Kurzai, Institute of Hygiene and Mikrobiology
University of Würzburg.
Academic education:
1965-1971 Studies of Medical Scienes at the Universities of Kiel (Germany) and Leeds (UK)
1972
Graduation (Dr. med.)
1973
MD-License (Kiel, Germany)
1973-1975 DFG-Scholarship for Immunology, Kiel (Germany)
Guest researcher at the Basel, Institute for Immunology (CH)
1975
Training of Dermatology at the University of Münster (Germany)
1982
Admission as a Doctor of Dermatology and Venerology
1984
Habilitation for Dermatology and Venerology
1986
Nomination as Professor for Dermatology (Münster)
1986
Authority to bear the additional designation „Allergology“
Prof. Dr. E.-B. Bröcker
since1992 Director of the Dept. of Dermatology, University Würzburg
Klinik und Poliklinik für Dermatologie,
1996-2005 Authority to bear the additional designations „Phlebology, Environmental
Venerologie und Allergologie der
Medicine, Dermatophatology“
Universität Würzburg
Functions and Awards (selected):
Josef-Schneider-Str. 2, Bau D8,
Editor of Dermatological Journals
97080 Würzburg
Johannes Fabry Medaille (1989)
Tel.: 0931-201-26351
Bayer. Maximiliansorden 2001
Fax: 0931-201-26462
Braun Falco Medaille 2006
[email protected]
ZINFbericht-final.P65
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3. Institutions of the Research Center for Infectious Diseases
PD Dr. med. Dr. rer. nat. Annette Kolb-Mäurer
1. Morphological plasticity of Candida
albicans is a major virulence factor. Using
pH-dependent dimorphism we show, that
human Dendritic Cells recognize filamentous forms and blastoconidia of a virulent C. albicans isolate (strain SC5314).
Heat inactivated and viable blastoconidia
are rapidly phagocytosed by human DC.
However, viable yeast cells start to filament
inside the DC at later stages of infection,
leading to penetration and loss of cellular
integrity. The cytokine burst of human DC
induced upon contact with Candida is
dominated by the granulocyte activating,
chemotactic factor IL-8 and the proinflammatory mediator TNF-α. Blastoconidia
induce markedly lower cytokine levels than
filamentous forms. Whereas IL-8 secretion
is mainly cell mass dependent, release of
TNF-α a major proinflammatory cytokine,
is clearly dependent on the morphology of
Candida. Taken together, these data show,
that morphological plasticity of C. albicans
is of major importance in the interaction
with human DC, but does most likely not
affect the IL-12 secretion of human DC. Engagement of environmentally regulated
dimorphism will enable the use of isogenic
strains for defining morphology-related
effects in future.
2. Meningococcal lipopolysaccharide is of
crucial importance for the pathogenesis of
invasive infection. We show, that sialylation
and elongation of the alpha-chain effectively
shields unencapsulated viable Neisseria
meningitidis from recognition by human
dendritic cells. In contrast, beta- and
gamma-chain of the LPS carbohydrate
moiety play only a minor role in the
interaction with DC. The protective function
of the LPS carbohydrate moiety for the
bacteria can be counteracted in vivo by
phase variation of the lgtA gene encoding
LPS glycosyltransferase A. Capsule expression protects N. meningitidis efficiently
from recognition and phagocytosis by DC
independent of the LPS structure. Despite
the significant impact of LPS structure on
the adhesion and phagocytosis of
N. meningitidis no differences were found
in terms of cytokine levels secreted by DC
ZINFbericht-final.P65
89
for IL1-beta, IL-6, IL-8, IL-12p40, TNF-alpha, IFN-gamma and GM-CSF. However,
significantly lower levels of the regulatory
mediator IL-10 were induced by encapsulated strains in comparison to
isogenic unencapsulated derivatives. The
use of truncated LPS isoforms in vaccine
preparations can therefore not only result
in attenuation but also in more efficient
targeting of DC. Further resolving this still
miscellaneous interaction will promote our
understanding of N. meningitidis virulence
and contribute to a rationale approach for
designing a vaccine against serogroup B
meningococci.
Selected references:
- Kurzai O, Schmitt C, Claus H, Vogel U, Frosch
M, Kolb-Maurer A. Carbohydrate composition
of meningococcal lipopolysaccharide modulates the interaction of Neisseria meningitidis
with human dendritic cells Cell Micro-biol.
2005;7:1319-34
- Kurzai O, Schmitt C. Brocker E, Frosch M,
Kolb-Maurer A. Polymorphism of Candida
albicans is a major factor in the interaction
with human dendritic cells Int J Med Microbiol. 2005; 295:121-7
- Schoen C, Kolb-Maurer A,Geginat G, Loffler
D, Bergmann B, Stritzker J, Szalay AA, Pilgrim
S, Goebel W. Bacterial delivery of functional
messenger RNA to mammalian cells Cell
Microbiol. 2005;7:709-24
- Schmidt E, Weissbrich B, Brocker EB,
Fleischer K, Goebeler M, Stich A. Orf followed
by erythema multiforme J Eur Acad Dermatol
VEnereol. 2006;20: 612-603
23.04.2007, 14:50
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3. Die Institutionen des Zentrums für Infektionsforschung
3.12 Chirurgische Klinik und
Poliklinik
Entwicklung humaner monoklonaler Antikörper als neue Therapie von chirurgischen
Infektionen, verursacht durch methicillinresistente und methicillin-sensible Staphylococcus aureus (MRSA und MSSA)
Zusammenfassung
Im Rahmen des bearbeiteten Projektes
sollen humane, monoklonale Antikörper für
die Therapie von Infektionen durch Staphylococcus aureus entwickelt werden.
Dazu wurden immundominante Antigene
von S. aureus identifiziert, charakterisiert
und spezifische Mutanten im Kleintier-
Arnulf Thiede
modell getestet. Beim Vergleich der
Immunreaktivität von Seren aus Patienten
vor und während einer Staphylokokkeninfektion wurde u.a. ein als IsaA bezeichnetes Antigen gefunden und für Immunisierungen rekombinant hergestellt. Ein
monoklonaler IgG2a Maus-Antikörper gegen IsaA konnte die Besiedlung von S.
aureus in einem Maus-Katheter-Modell signifikant verringern. In weiteren Versuchen
wird gegenwärtig die Wirksamkeit von weiteren spezifischen monoklonalen Antikörpern getestet. Genetische Untersuchungen
zur Regulation der isaA-Expression zeigten, dass die Produktion dieses Proteins
von globalen Virulenzregulatoren wie sarA
und sigB kontrolliert wird. Eine spezifische
SigB-Mutante war im Maus-Kathetermodell
20. August 1942
1949-1958
1958-1962
1968-1969
1970
1972
Prof. Dr. med. Arnulf Thiede
Universitätsklinikum Würzburg
Chirurgische Klinik und Pöliklinik
Zentrum Operative Medizin
Oberdürrbacher Str. 6
D-97080 Würzburg
Tel.: ++49 (0)931-201-31000
primary and secondary school in Kiel
study of medicine at Kiel, Berlin, Frankfurt, Tübingen
house officer time in Berlin, Kiel, promotion and dissertation as Dr. med.
surgical residency program in Kiel (until 1987)
foundation of a microsurgical laboratory for experimental transplantation
research and microsurgical research
1973-1987 project leader in various surgical transplantation research programs
supported by Sonderforschungsbereich 111 of DFG (German research
council)
1976
habilitation for university lecturer, consultant, department of general
surgery University of Kiel
1976
Langenbeck award of the German society of surgery
1979
foundation of the transplant center Kiel
1980
associate professor of surgery
1975,79,
study visits in USA (3 x), Great Britain (2 x)
1981,84,88 Thailand (2 x)
1983
head consultant department of general surgery university of Kiel
1985
continuous referee of the DFG (German research council); German
ministery of education, science, research and technology (BMBF);
second director department of general surgery university of Kiel
1987
visiting professor Jichi University, Japan
1988
medical director of the surgical clinic of Friedrich Ebert Hospital,
Neumünster, Germany
1988/89
member of the commission of the German health authority for suture
materials: new edition of the European pharmacopoe
1991
director of the department of surgery of the university of Würzburg, Germany
1994/96
visiting professor in Curitiba, Brasil
1996
chairman of the Bavarian surgical society
1996/97
chairman of the surgical research groups in the interdisciplinary center
for clinical research (IZKF) of the Julius-Maximilians-Universität Würzburg
2000/2001 president of the German Society of wound healing
up to now more than 400 publication in clinical and experimental surgery in national and
international books and journals
Fax: ++49 (0)931-201-31009
[email protected]
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3. Institutions of the Research Center for Infectious Diseases
deutlich attenuiert. Alle bisherigen Daten
unterstreichen die Bedeutung einer effektiven Wirts-Immunreaktion gegen IsaA für
eine Abwehr von S. aureus.
1) Analyse von Zielstrukturen für humane
monoklonale Antikörper
Es wurde nach immunodominanten Antigenen gesucht, die als potenzielle Targetstruktur für eine Immunotherapie geeignet
sein könnten. Dazu wurden zwei Ansätze
angewendet (i) Screening von Patientenseren mit Reaktivität gegen S.aureus-spezifische Faktoren und (ii) Expression von
Staphylokokkenproteinen in einer Expressionsgenbank.
2) Untersuchungen von Staphylokokkenmutanten in Kleintiermodellen
In diesem Teil des Projektes wurde die invivo Bedeutung von identifizierten immunodominanten Proteinen für die Entstehung
und Ausbreitung einer Infektion studiert.
Dafür wurden die Gene isaA, isaB und sigB
mutagenisiert. Diese Gene kodieren für
immunodominante Zellkomponenten von
S. aureus (IsaA, IsaB) oder sind an der
Regulation dieser Faktoren beteiligt (SigB).
Es wurde ein Tiermodell entwickelt, das
die Analyse pathophysiologischer Prozesse bei typischen S. aureus-Infektioen erlaubt. In diesem Modell wird einer Maus
ein Katheter in die Vena jugularis implan-
tiert. Über diesen venösen Zugang werden
107 S. aureus-Zellen inokuliert, von denen
einige an der Katheterwand adherieren,
einen Biofilm bilden und von dort in das
Gewebe dissiminieren. Bei diesen Abläufen sind verschiedene Virulenzfaktoren involviert und das Geschehen spiegelt sehr
gut pathophysiologische Prozesse bei
nosokomialen Infektionen wieder. In einem
ersten Versuchsansatz wurden ein biofilmbildender S. aureus Stamm und dessen
isogene SigB-Mutante eingesetzt. Sigma
B ist ein alternativer Sigma-Faktor, der auch
an der Regulation der IsaA-Expression
beteiligt ist. Nach 120 h wurde die Bakterienlast in den Organen und in dem Katheter bestimmt und die Biofilmbildung
durch Elektronenmikroskopie untersucht.
Der Wildtypstamm konnte signifikant häufiger aus den einzelnen Organsystemen
isoliert werden als der Mutantenstamm
und es konnte somit eindeutig die eingeschränkte Virulenz der SigB-Mutante gezeigt werden. In einem zweiten Tiermodell
kann mit Hilfe eines biolumineszierenden
S. aureus Stammes die Dynamik des
Infektionsprozesses visualisiert werden. In
diesem Weichteil-Infektionsmodell wurden
verschiedene Mutanten und therapeutische monoklonale Antikörper getestet. In
Fig.1 ist der abgeschwächte Infektionsverlauf einer IsaA Insertionsmutante oder
nach Gabe eines anti-IsaA Antikörpers
(MAB-ISAA29) gargestellt.
Education:
1976 – 1988 Gymnasium, Berlin/ Germany
1988
Abitur (roughly equivalent to A levels)
1990 – 1995 Ernst-Moritz-ArndtUniversity,Greifswald/ Germany
Study of Human Medicine state examination
1996
medical degree from the University of Greifswald/ Germany
Work Experience:
1990
preclinical year, Charité, Berlin/ Germany
1995 – 1996 practical year, Department of Surgery, University of Southern California,
Los Angeles/ USA, Department of Vascular Surgery, Albert Einstein
College of Medicine and Montefiore Medical Center, New York/ USA,
University of Nebraska, Omaha/ USA
1996 – 1998 first year resident, Department of General Surgery, University of Würzburg/
Germany
1998 – 1999 scientific assistant, Institute for Molecular Infection Biology,
University of Würzburg/ Germany
since 1999 resident, Department of General Surgery, University of Würzburg/ Germany
91
Udo Lorenz
7. Juli 1969
Dr. Udo Lorenz
Universitätsklinikum Würzburg
Chirurgische Klinik und Pöliklinik
Zentrum Operative Medizin
Oberdürrbacher Str. 6
D-97080 Würzburg
Tel.: ++49 (0)931-201-31000
Fax: ++49 (0)931-201-31009
[email protected]
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3. Die Institutionen des Zentrums für Infektionsforschung
3) Passive Immunisierung im MausKathetermodell
Mit Hilfe des Maus-Kathetermodells und
des Biolumineszenz-Modells soll geprüft
werden, inwieweit monoklonale Antikörper
allein oder in Kombination in der Lage sind
einen Immunschutz zu induzieren.
Ein monoklonaler Antikörper wurde gegen
das IsaA-Protein generiert und in einem
Ratten-Infektionsmodell getestet. Es zeigte sich, dass eine Anti-IsaA Ak-Gabe die
Infektion mit S. aureus zurückdrängen
kann. Dieser Effekt wurde durch eine beschleunigte Phagozytose durch humane
polymorphkernige Granulozyten und durch
eine direkte Blockierung von IsaA erreicht.
Die Blockierung von IsaA, einer lytischen
Transglykosylase, führt wahrscheinlich zu
einer gestörten Zellwandsynthese von S.
aureus.
4) „knock out“ Strategie im Maus-Kathetermodell
In diesem Teilprojekt sollen verschiedene
humane, wirtsspezifische Faktoren und
deren Einfluß für den Infektionsverlauf mit
S. aureus untersucht werden. Durch gezielte Inaktivierung von Genen, zum Beispiel knock-out für Plasmafibrinogen in
Mäusen, lässt sich der Effekt im KatheterSepsis-Modell studieren.
3.12 Surgical Clinic with Outpatients’ Department
Summary
In the context of the project, human
monoclonal antibodies shall be developed
for the therapy of serious infections caused
by Staphylococcus aureus. Immuno-dominant antigens of S. aureus were identified,
characterized and specific mutants tested
in a small animal model. At the comparison
of the immunoreactivity of sera from
patients before and during a staphylococcus infection an antigen described as
IsaA was found and produced recombinantly for immunizations. A monoclonal
IgG2a mouse antibody against IsaA could
ZINFbericht-final.P65
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significantly reduce the settlement of S.
aureus in organs in a catheter-sepsis
model. In further tests, the effectiveness of
different specific monclonal antibodies
should be presented. Genetic examinations to the regulation showed that the
production of IsaA is controlled by global
virulence regulators like sarA and sigB. A
specific SigB-mutant was considerably
attenuated in the mouse catheter model.
All previous data underline the significance
of an effective host immune response
against IsaA for a defence of S. aureus.
1)Analysis of target structures of Staphylococcus aureus for the development of human monoclonal antibodies
Putative immunodominant antigens were
investigated in order to evaluate whether
or not these antigens can be used as
targets for the development of immunotherapeutics. Two approaches have been
applied: (i) Screening of sera of patients
and identification of immunodominant
antigenic factors of Staphylococcus aureus
(ii) Construction of an expression library of
S. aureus proteins.
2) Investigation of mutants of Staphylococcus aureus in experimental models
This project part aims at investigating the
role of different immunodominant antigens
in-vivo. For this purpose several deletion
mutants were constructed including mutations of isaA, isaB and sigB. These genes
were identified either as important immunodominant antigens (IsaA, IsaB) or
may play a major role in the regulation of
virulence-associated genes.
Moreover, a catheter-related infection
model in mouse was developed which
allows the analysis of pathophysiological
processes typical seen during invasive S.
aureus infections. In this model system, a
catheter was implanted into the jugular vein
of mice. Following implantation S. aureus
bacteria were given via the catheter forming
a strong biofilm inside the lumen of the
catheter. Some bacteria can afterwards
leave the biofilm and disseminate into
several organs forming multiple abscesses. Several virulence factors are
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3. Institutions of the Research Center for Infectious Diseases
involved in the pathogenesis of catheterrelated infections. In a first attempt, the role
of the alternative sigma factor SigB during
pathogenesis of catheter-related infections
was investigated using the animal model.
The biofilm-forming wildtype strain and its
isogenic mutant was applicated via the
implanted catheter and the outcome of the
infection was determined 120 h after
infection. The number of bacteria in the
organs was investigated using quantitative plate counting. These experiments
turned out that the SigB wildtype was
significantly more virulent than its isogenic
mutant suggesting a pivotal role of SigB
during the infection process. Further
studies are under way to investigate the
role of IsaA and IsaB in the infection
process. In a second animal model,
bioluminescent S. aureus were used to
visualize the dynamics of the infection
process. In this soft tissue infection model
different mutants and therapeutic monoclonal antibodies will be tested. The
impaired course of infection of an IsaA
insertion mutant and after anti IsaA antibody treatment (MAB-ISAA29) is displayed
in Figure 1.
93
3) Passive immunization studies
With the help of the mouse catheter model
and the bioluminescence model it shall be
checked how far monoclonal antibodies
alone or into combination are able to induce
an immune protection. A monoclonal
antibody was generated against the IsaA
protein and tested in a mouse infection
model. MAB-ISAA29 enhances significant
S. aureus containment in antibody treated
mice compared to control mice.
The proposed action of MAB-ISAA29 is
evoked by antibody-mediated phagocytosis and by preventing the completion
of the nascent cell wall of S. aureus.
4) „ knock out„ strategy in the mouse
catheter model
In this partial project different humane, host
specific factors and their influence shall be
examined for the infection course with S.
aureus. By a specific inactivation of genes,
for example knock out for plasma-fibrinogen in mice, the effect can be studied in
the catheter sepsis model.
Fig. 1: Soft tissue infection
model. Explanation, see point 2)
in the text.
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3. Die Institutionen des Zentrums für Infektionsforschung
3.13 Die Tropenmedizinische
Abteilung der Missionsärztlichen Klinik
Weltweit, aber auch in Deutschland spielen tropenmedizinische Problemfelder
eine zunehmende Rolle. Gesundheitsdienste, die mit tropischen Infektionskrankheiten konfrontiert werden, sind oftmals schnell überfordert, worunter die Versorgung von Patienten leidet. Die medizinische Forschung im klassischen Sinn
verfolgt den Ansatz, grundlagenwissenschaftliche Erkenntnisse über die Erreger
zu gewinnen, die Pathophysiologie der Erkrankungen zu verstehen oder theoretische Ansätze für neue Wirkstoffe und
Therapiekonzepte zu entwickeln. Eine andere Möglichkeit, auf die Herausforderungen der Tropenmedizin zu reagieren, besteht in dem Versuch medizinisches, pflegerisches und labortechnisches Personal
in der Versorgung von Patienten und in der
optimalen Ausnutzung der vorhandenen
Ressourcen zu unterrichten.
In genau dieses Feld hat sich in den letzten Jahren die Tropenmedizinische Abtei-
August Stich
09. September 1960
PD Dr. med. August Stich
Missionsärztliches Institut
Arbeitsgruppe Tropenmedizin und
Seuchenbekämpfung
Hermann-Schell-Str. 7
97074 Würzburg
Tel.: 0931 - 80 48 523
Fax: 0931 - 80 48 530
[email protected]
ZINFbericht-final.P65
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lung der Missionsärztlichen Klinik in enger
Kooperation mit den Arbeitsgruppen des
Missionsärztlichen Instituts Würzburg begeben. In den vergangenen zehn Jahren wurden zahlreiche Unterrichtseinheiten zu verschiedenen Themenstellungen und für ganz
verschiedene Zielgruppen organisiert. Das
Spektrum reicht von Kursen über den Einsatz angepasster Labormethoden in Gesundheitseinrichtungen des ländlichen Afrika, die Einführung der Ultraschalldiagnostik
in Innerer Medizin und Geburtshilfe in afrikanischen Distriktkrankenhäusern, der Unterweisung ausreisender Entwicklungshelfer
über die medizinischen Realitäten in ihrem
Gastland oder eine Internet-basierte interaktive Lerneinheit zum Thema HIV/AIDS bis
hin zu einem Kursus über das Management
hochkontagiöser Erkrankungen in Deutschland, der in Zusammenarbeit mit dem Robert-Koch-Institut inzwischen regelmäßig
durchgeführt wird. In den vergangenen zehn
Jahren wurden über 3000 Angehörige von
Medizinberufen über diese Ausbildungseinheiten erreicht. In diese Zahl nicht mit eingerechnet sind Vorlesungen und medizini-
Academic Career:
1978-1985 Studies of Medicine at the Universtiy of Wuerzburg
1986
PhD in ophthalmology
1985-1991 Medical training and Announcement to an ophthalmology
1988
Development aid in Zimbabwe
1991-1993 Postgradual Study in London, Master of Science in Clinical Tropical Medicine
1993
Application in Somalia
1994-1995 Projekt leader of an development aid programme for Médecins sans
Frontières in Kambodscha
1996
Additional education Tropical Medicin
1995-1999 Medical Training to an Internist
1999-2001 Research fellow at the Department of Parasitology of the University
Heidelberg
since 2001 Project group leader „Klinische Tropenmedizin am Missionsärztlichen
Institut“ Würzburg
since 2004 Head of Department „Klinische Tropenmedizin am Missionsärztlichen
Institut“ Würzburg
Functions and Awards:
1992
Duncan-Award of the DTM&H-course of the Royal College of Physicians
1992
Frederick Murgatroyd Award of London School of Hygiene and Tropical
Medicine
since 1996 Local Secretary of the Royal Society of Tropical Medicine and Hygiene für
Deutschland
1997-2000 Member of the Organizing commitee „Ärzte ohne Grenzen“ (Friedensnobel
preis 1999)
since2002 Member of „Leitlinienausschuss der Deutschen Gesellschaft für Tropen
medizin und Internationale Gesundheit“
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3. Institutions of the Research Center for Infectious Diseases
schen Weiterbildungsveranstaltungen für
einheimische Studenten und Ärzte.
Daneben sind mehrere Projekte entstanden, die neue Erkenntnisse und Techniken in tropischen Ländern einsetzen und
mit wissenschaftlichen Methoden untersuchen. Diese angewandte Forschung
(implementation research) hat sich vor allem auf die beiden großen tropischen Infektionskrankheiten Malaria und Schlafkrankheit fokalisiert. Schwerpunkt sind
dabei Untersuchungen zum Einsatz insektizidimprägnierter Moskitonetze zur
Malariakontrolle in mehreren afrikanischen
Ländern, Studien zu Verlauf und Epidemiologie der Schlafkrankheit in Angola sowie
in-vitro-Untersuchungen neuer Wirkstoffe
gegen Trypanosomen.
3.13 The Department of Tropical Medicine of the Medical
Mission Hospital
Tropical medicine is playing an increasing
role globally, but also in Germany. Health
services dealing with tropical infections are
often overstretched. This might lead to
insufficient care for the patients. Classical
medical research aims at acquiring new
knowledge in basic sciences, at understanding the pathophysiology of diseases
or at developing theoretical approaches for
new drugs and treatment concepts.
Another possibility to react to the challenges in tropical medicine, however, is the
attempt to offer training to medical, nursing
and laboratory personnel on how to
improve the care of their patients and how
to make the best use of existing resources.
This is exactly the field in which the Tropical Department of the Medical Mission Hospital in close cooperation with the units of
the Medical Mission Institute is engaged.
In the past ten years, numerous training
units on various topics and for different
target groups have been organised. Their
spectrum ranges from courses in the use
of appropriate laboratory techniques for
ZINFbericht-final.P65
95
health institutions in rural Africa, the
introduction of diagnostic ultrasound in
internal medicine and obstetrics for African
district hospitals, to courses for development aid workers to confront them
with the medical realities of their host
countries, an internet-based, interactive
training module on HIV/AIDS and workshops on the management of highly
contagious diseases. In the past ten years,
more than 3,000 health professionals
could benefit from those training units. This
figure still excludes medical students and
doctors who participated in regular lecture
series, courses and seminars offered by
our institution.
In addition, projects have been implemented to develop and test new approaches and tools in tropical countries
with scientific methods. This „implementation research“ is focusing on the two
big tropical infectious diseases malaria
and human African trypanosomiasis
(sleeping sickness). Current research
priorities are studies on the use of
insecticide-impregnated bed nets for
malaria control in various African countries,
on the clinical presentation and the
epidemiology of sleeping sickness in Angola and on cytotoxicity of various new
compounds against trypanosomes using
in vitro screening assays.
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96
3. Die Institutionen des Zentrums für Infektionsforschung- Publikationen
3.14 Publications of the Institutions of the Research Center for
Infectious Diseases: 2005/2006
3-1 Chair of Virology
Abt, M., Müller, N., and Schneider-Schaulies, S. (2006) DC in measles pathogenesis. John Wiley & Son’s Dendritic cells. 855868.
Avota, E., Harms, H., and Schneider-Schaulies, S. (2006) Measles virus induces expression of SIP110, a constitutively membrane
clustered lipid phosphatase, which inhibits T cell proliferation. Cell Microbiol 8: 1826-1839.
Beddows, S., Franti, M., Dey, A.K., Kirschner, M., Iyer, S.P., Fisch, D.C., Ketas, T., Klasse, P.J., Maddon, P.J., Olson, W.C and Moore,
J.P. (2007) A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric
human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120. Virology 360: 32940.
Beddows, S., Kirschner, M., Campbell-Gardener, L., Franti, M., Dey, AK., Iyer, S.P., Maddon, P.J., Paluch, M., Master, A., Overbaugh,
J., VanCott, T., Olson, W.C., Moore, J.P. (2006) Construction and characterization of soluble, cleaved, and stabilized trimeric
Env proteins based on HIV type 1 Env subtype A. AIDS Res Hum Retroviruses 22: 569-79.
Beddows, S., Schulke, N., Kirschner, M., Barnes, K., Franti, M., Michael, E., Ketas, T., Sanders, R.W., Maddon, P.J., Olson, W.C.,
and Moore, J.P. (2005) Evaluating the immunogenicity of a disulfide-stabilized, cleaved, trimeric form of the envelope
glycoprotein complex of human immunodeficiency virus type 1. J Virol 79: 8812-27.
Bender, F.L.P., Fischer, M., Funk, N., Orel, N., Rethwilm, A., and Sendtner, M. (2007) High-efficiency gene transfer into cultured
embryonic motoneurons using recombinant lentiviruses. Histochem Cell Biol 127: 439-48.
Bodem, J., Kräusslich, H.G., and Rethwilm, A. (2007) Acetylation of the foamy virus transactivator Tas by PCAF augments
promoter-binding affinity and viral transcription. J Gen Virol 88: 259-63.
Cartellieri, M., Rudolph, W., Herchenröder, O., Lindemann, D., and Rethwilm, A. (2005) Determination of the relative amounts of
gag and pol proteins in foamy virus particles. Retrovirology 2: 44.
Cartellieri, M., Herchenröder, O., Rudolph, W., Heinkelein, M., Lindemann, D., Zentgraf, H., and Rethwilm, A. (2005) N-terminal
gag domain required for foamy virus particle assembly and export. J Virol 79: 12464-12476.
Cigler, P. ,Kozisek, M., Rrezácová, P., Brynda, J., Otwinovski, Z., Pokorná, J., Plesek, J., Grüner, B., Dolecková, L., Masa, M.,
Sedládek, J., Bodem, J., Kräusslich, H.G., Král, V. and Konvalinka, J. (2005) From non-peptide towards non-carbon protease
inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. PNAS 102: 15394-9.
De Witte, L., Abt, M., Schneider-Schaulies, S., Van Kooyk, Y., and Geijtenbeek, T.B.H. (2006) Measles virus targets DC-SIGN to
enhance dendritic cell infection. J Virol 80: 3477-3486.
Doerries, K. (2006) Human polyomavirus JC and BK persistent infection. Adv Exp Med Biol 577: 102-16.
Gronen, F., Ruprecht, K., Weissbrich, B., Klinker, E., Kroner, A., Hofstetter, H.H., and Rieckmann, P. (2006) Frequency analysis of
HLA-B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls.
J Neuroimmunol 185-92.
Grünblatt, E., Koutsilieri, E., Hoyer, S., and Riederer, P. (2006) Gene expression alterations in brain areas of intracerebroventricular
streptozotocin-treated rat. J Alzheimer´s disease 9: 261-271.
Grünblatt, E., Schlosser, R., Fischer, P., Fischer, M.O., Li, J., Koutsilieri, E., Wichart, I., Sterba, N., Rujescu, D., Moller, H.J.,
Adamcyk, W., Dittrich, B., Muller, F., Oberegger, K., Gatterer, G., Jellinger, K.J., Mostafaie, N., Jungwirth, S., Huber, K., Tragl,
K.H., Danielczyk, W., and Riederer, P. (2005) Oxidative stress related markers in the „VITA“ and the centenarian projects.
Neurobiol Aging 26: 429-438.
Heinkelein, M., Hoffmann, U., Lücke, M., Imrich, H., Müller, J.G., Meixensberger, J., Westphal, M., Kretschmer, A., and Rethwilm,
A. (2005) Experimental therapy of allogeneic solid tumours induced in athymic mice with suicide gene-transducing replicationcompetent foamy virus vectors. Cancer Gene Ther 12: 947-953.
Inhoff, O., Doerries, K., Doerries, R., Scharf, J., Groden, C., Schadendorf, G., and Schadendorf, D. (2006) Disseminated Cutaneous
Kaposi Sarcoma and Progressive Multifocal Leukencephalopathy in a Patient with Idiopathic CD4+ T-Lymphocytopenia.
Archives of Dermatology (in press).
Jackson, G.S., McKintosh, E., Flechsig, E., Prodromidou, K., Hirsch, P., Linehan, J., Brandner, S., Clarke, A.R., Weissmann, C.,
and Collinge, J. (2005) An enzyme-detergent method for effective prion decontamination of surgical steel. J Gen Virol 86:
869-78.
Kirschner, M., Montazem, A., Hilaire, H.S., and Radu, A. (2006) Long-term culture of human gingival keratinocyte progenitor cells
by down-regulation of 14-3-3 sigma. Stem Cells Dev 15: 556-65.
Kirschner, M., Monrose, V., Paluch, M., Techodamrongsin, N., Rethwilm, A., and Moore J.P. (2006) The production of cleaved,
trimeric human immunodeficiency virus type 1, (HIV-1) envelope glycoprotein vaccine antigens and infectious pseudoviruses
using linear polyethylenimine as a transfection reagent. Protein Expr Purif 48: 61-8.
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97
Koutsilieri, E., Arendt, G., Neuen-Jacob, E., Scheller, C., Grünblatt, E., and Riederer, P. (2006) HIV dementia: a neurodegenerative disorder with viral etiology. Handbook of Neurochemistry and Molecular Neurobiology, 3rd ed. (in press).
Kraus, M.R., Schafer, A., Bentink, T., Scheurlen, M., Weissbrich, B., Al-Taie, O., and Seufert, J. (2005) Sexual dysfunction in
males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression? J
Endocrinol 185: 345-352.
Lehmann, C., Duprex, P., Krohne, G., Rima, B.K., and Schneider-Schaulies, S. (2007). Measles virus M and F proteins
associate with detergent resistant membrane fractions and independently promote formation of virus-like particles. J.
Gen. Virol. 88: 243-50.
Lehmann, C., Shishkova, Y., and Schneider-Schaulies, S. (2007). Viruses and dendritic cells: enemy mine. Cell Microbiol 9:
279-89.
Li, J., Scheller, C., Koutsilieri, E., Griffiths, F., Beart, P.M., Mercer, L.D., Halliday, G., Kettle, E., Rowe, D., Riederer, P., Gerlach, M.,
Rodriguez, M., and Double, K.L. Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and glial cells (2005). J Neurochem 95: 599-608.
Lüftenegger, D., Picard-Maureau, M., Stanke, N., Rethwilm, A., and Lindemann, D. (2005) Analysis and function of prototype
foamy virus envelope N-glycosylation. J Virol 79: 7664-7672.
Maschmann, J., Hamprecht, K., Weissbrich, B., Dietz, K., Jahn, G., and Speer, C.P. (2006) Freeze-thawing of breast milk does
not prevent cytomegalovirus transmission to a preterm infant. Arch Dis Child Fetal Neonatal 91: F288-290.
Mössner, R., Yun, S.W., Lesch, K.P., Gerlach, M., Klein, M.A., and Riederer, P. (2006) Unaltered susceptibility to scrapie in
serotonin transporter deficient mice. Neurochem Int 49: 454-8.
Müller, N., Avota, E., Schneider-Schaulies, J., Krohne, G., and Schneider-Schaulies, S. (2006) Measles virus contact impedes
cytoskeletal remodeling required for T cell adhesion and immunological synapse formation. Traffic 7: 1-10.
Müller, N., Avota, E., Schneider-Schaulies, J., Harms, H., Krohne, G., and Schneider-Schaulies, S. (2006) Measles virus
contact impedes cytoskeletal remodeling associated with T cell adhesion, spreading and CD3 clustering in the
immunological synapse. Traffic 7: 1-10.
Nowrouzi, A., Dietrich, M., Klanke, C., Heinkelein, M., Rammling M., Dandekar, T., Kalle, C., and Rethwilm, A. (2006) Genomewide mapping of foamy virus integrations in a human cell line. J Gen Virol 87: 1339-1347.
Obojes, K., Andres, O., Kim, K.S., Däubener, W., and Schneider-Schaulies, J. (2005) Indolamine 2,3-dioxygenase (IDO)
mediates cell type specific anti-measles virus activity of gamma interferon. J Virol 79: 7768-7776.
Peters, K., Wiktorowicz, T., Heinkelein, M., and Rethwilm, A. (2005) RNA and protein requirements for the incorporation of pol
protein into foamy virus particles. J Virol 79: 7005-7013.
Rethwilm., A (2005): Foamy Viruses. Topley & Wilson’s Microbiology, 10th ed., 1304-1321.
Reuter, T., Weissbrich, B., Schneider-Schaulies, S., and Schneider-Schaulies, J. (2006). RNA interference with measles virus
polymerase mRNA efficiently prevents, and with matrix protein mRNA enhances viral transcription. J Virol 80: 5951-5957.
Rohayem., J., Dumke, R., Jäger, K., Schröter-Bobsin, U., Mogel, M., Kruse, A., Jacobs, E., and Rethwilm, A. (2006) Viral load in
the river Elbe during the flood in August 2000. Intervirology 49: 370-376.
Rohayem, J., Münch, J. and Rethwilm, A. (2005) Recombination in the norovirus capsid gene. J Virol 79: 4977-4990.
Rueger, M.A., Miletic, H., Dörries, K., Wyen, C., Deckert, M., Fätkenheuer, G., Jacobs, A.H. (2006) Long-term remission in
progressive multifocal leukoencephalopathy caused by idiopathic CD4+ T-lymphocytopenia: a case report. Clinical
Infectious Diseases 42: 53-56.
Ruprecht, K., Obojes, K., Wengel, V., Gronen, F., Perron, H., Schneider-Schaulies, J., and Rieckmann, P. (2006) Regulation of
human endogenous retrovirus W protein expression by herpes simplex virus type 1: Implications for multiple sclerosis.
J Neurovirol 12: 65-71.
Santibanez, S., Niewiesk, S., Heider, A., Schneider-Schaulies, J., Berbers, G.A.M., Zimmermann, A., Halenius, A., Wolbert, A.,
Deitemeier, I., Tischer, A., and Hengel, H. (2005) Probing neutralzing antibody responses against emerging measles
viruses (MV): immune selection of MV by H protein-specific antibodies? J Gen Virol 86: 365-374.
Scheller, C., Knoferle, J., Ullrich, A., Prottengeier, J., Racek, T., Sopper, S., Jassoy, C., Rethwilm, A., and Koutsilieri, E. (2006)
Caspase inhibition in apoptotic T cells triggers necrotic cell death depending on the cell type and the proapoptotic
stimulus. J Cell Biochem 97:1350-1361.
Scheller, C., Riederer, P., Gerlach, M., and Koutsilieri E. (2006). Induction of proinflammatory signaling due to inhibition of
apoptosis in T cells-implications for the CNS. J Neural Transm 71: 45-51.
Scheller, C., Ullrich, A., Lamla, S., Dittmer, U., Rethwilm, A., and Koutsilieri, E. (2006) Dual activity of phosphorothioate CpGoligodeoxynucleotides on HIV: Reactivation of latent provirus and inhibition of productive infection in human T cells. Ann
N Y Acad Sci 1091: 540-7.
Scheller, C., Sopper, S., Jenuwein, M., Neuen-Jacob, E., Tatschner, T., Grünblatt, E., ter Meulen, V., Riederer, P., and Koutsilieri,
E. (2005) Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia
activation. J Neurochem 95: 377-387.
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Schneider-Schaulies, J., Schneider-Schaulies, S., and ter Meulen, V. (2005) Infections of the Central Nervous System. Topley
& Wilson’s Virology. 10th ed., 1403-1442.
Schneider-Schaulies, S., and Dittmer, U. (2006). Silencing T cells or T cell silencing: concepts in virus-induced
immunosuppression. J Gen Virol 87: 1423-38.
Schneider-Schaulies, S., and Bellini, W.J (2005) Morbilliviruses: Measles virus. Topley & Wilson’s Virology, 10th ed., 712-742.
Schmidt, E., Weissbrich, B., Brocker, E.B., Fleischer, K., Goebeler, M., and Stich, A. (2006) Orf followed by erythema multiforme.
J Eur Acad Dermatol Venereol 20: 612-613.
Singethan, K., Topfstedt, E., Schubert, S., Duprex, W.P., Rima, B.K., and Schneider-Schaulies, J. (2006) CD9-dependent
regulation of canine distemper virus (CDV)-induced cell-cell fusion segregates with extracellular domain of the
haemagglutinin. J Gen Virol 87: 1635-1642.
Schubert, S., Moeller, K., Wiese, S., Duprex, P.W., Rima, B.K., Niewiesk, S., and Schneider-Schaulies, J. (2006) A mouse
model of persistent brain infection with recombinant measles virus. J Gen Virol 87: 2011-2019.
Stange, A., Manigel, I., Peters, K., Heinkelein, M., Stange, N., Rethwilm, A., Zentgraf, H., and Lindemann, D., (2005)
Characterization of prototypic foamy virus late assembly domain motifs and their role in particle egress and infectivity. J
Virol 79: 5466-5476.
Sticht, J., Humbert, M., Findlow, S., Bodem, J., Müller, B., Dietrich, U., Werner, J., and Kräusslich, H.G. (2005) A peptide inhibitor
of HIV-1 assembly in vitro. Nat Struct Biol 12: 671-7.
Weissbrich, B., Neske, F., Schubert, J., Tollmann, F., Blath, K., Blessing, K., and Kreth, H.W. (2006) Frequent detection of
bocavirus DNA in German children with respiratory tract infections. BMC Infect Dis 6: 109.
Winzer, R., Langmann, P., Zilly, M., Tollmann, F., Schubert. J., Klinker, H., and Weissbrich, B. (2005) No influence of the Pglycoprotein polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment
naive HIV-positive patients. Ann Clin Microbiol Antimicrob 4: 3.
Yun, S.W., Gerlach, M., Riederer, P., and Klein M.A. (2006) Oxidative stress in the brain at early preclinical stages of mouse
scrapie. Exp Neurol 201: 90-8.
3-2 Chair of Immunology:
Beaudette-Zlatanova BC, Whalen B, Zipris D, Yagita H, Rozing J, Groen H, Benjamin CD, Hunig T, Drexhage HA, Ansari MJ, Leif
J, Mordes JP, Greiner DL, Sayegh MH, Rossini AA. (2006) Costimulation and autoimmune diabetes in BB rats. Am J
Transplant. May;6(5 Pt 1):894-902.
Berberich-Siebelt, F., Berberich, I., Andrulis, M., Santner-Nanan, B., Jha, M. K., Klein-Hessling, S., Schimpl, A., and Serfling, E.
(2006) SUMOylation interferes with CCAAT/enhancer-binding protein beta-mediated c-myc repression, but not IL-4 activation
in T cells. J Immunol 176: 4843-4851
Berger, S., Wolfer, D.P., Selbach, O., Alter, H., Erdmann, G., Reichardt, H.M., Chepkova, A.N., Welzl, H., Haas, H.L., Lipp, H.P., and
Schütz, G. (2006) Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity. Proc Natl Acad Sci USA 103:
195-200.
Beyersdorf, N., Gaupp, S., Balbach, K., Schmidt, J., Toyka, K.V., Lin, C.H., Hanke, T., Hunig, T., Kerkau, T., and Gold, R. (2005a)
Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune
encephalomyelitis. J Exp Med 202: 445-455.
Beyersdorf, N., Hanke, T., Kerkau, T., and Hünig, T. (2005). Superagonistic anti-CD28 antibodies: potent activators of regulatory
T cells for the therapy of autoimmune diseases. Annals of the Rheumatic Diseases 64;91-95.
Beyersdorf, N., Hanke, T., Kerkau, T., and Hünig, T. (2006). CD28 superagonists put a break on autoimmunity by preferentially
activating CD4+CD25+ regulatory T cells. Autoimmunity Reviews 5:40-45.
Beyersdorf N, Balbach K, Hunig T, Kerkau T. (2006) Large-scale expansion of rat CD4 CD25 T cells in the absence of T-cell
receoptor stimulation. Immunology
Cao, Yi, Catherine Toben, Shin-Yooung Na, Kirsten Stark, Lars Nitschke, Alan Peterson, Ralf Gold, Anneliese Schimpl and
Thomas Hünig (2006). Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin
in oligodendrocytes. Eur. J. Immunol. 36:207-215.
Dennehy KM, Elias F, Zeder-Lutz G, Ding X, Altschuh D, Luhder F, Hunig T. (2006) Cutting edge: monovalency of CD28
maintains the antigen dependence of T cell costimulatory responses. J Immunol. May 15;176(10):5725-9.
Dennehy KM, Elias F, Na S-Y, Fischer K-D, Hünig T, Lühder F. Mitogenic CD28 signals require the exchange factor Vav1 to
enhance TCR signaling at the SLP-76-Vav-Itk signalosome. The Journal of Immunology, in press.
Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR, Yu C, Fennelly JA, Vowles C, Hanke T, Walse B, Hunig T,
Sorensen P, Stuart DI, Davis SJ. (2005) Crystal structure of a soluble CD28-Fab complex. Nat Immunol. Mar;6(3):271-9.
Herrmann, M.M., Gaertner, S., Stadelmann, C., van den Brandt, J., Boscke, R., Budach, W., Reichardt, H.M., and Weissert, R.
(2005) Tolerance induction by bone marrow transplantation in a multiple sclerosis model. Blood 106: 1875-1883.
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99
Herold, M.J., McPherson, K.G., and Reichardt, H.M. (2006) Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci
63: 60-72.
Herold, M. J., Zeitz, J., Pelzer, C., Kraus, C., Peters, A., Wohlleben, G., and Berberich, I. (2006) The stability and anti-apoptotic
function of A1 are controlled by its C terminus. J Biol Chem 281: 13663-13671
Hünig, T. and Dennehy, K. (2005). CD28 superagonists: Mode of action and therapeutic potential. Immunology Letters 100
(2005) 21-28.
Kerstan, A. and Hünig, T. (2005). Cyclosporin A abolishes CD28-mediated resistance to apoptosis via superinduction of
caspase-3. in revision.
Kerstan A, Armbruster N, Leverkus M, Hünig T, (2006) Cyclosporin A abolishes CD28-mediated resistance to CD95-induced
apoptosis via superinduction of caspase-3. J. Immunol. 177: 7689-7697
Na, Shin-Young, Yi Cao, Catherine Toben, Kevin Dennehy, Lars Nitschke, Christine Stadelmann, Ralf Gold, Anneliese Schimpl,
Thomas Hünig (2006). Regulatory T-cells prevent spontaneous CD8 T-cell-mediated autoimmune encephalomyelitis.
Submitted.
Pyz, E., Naidenko, O., Miyake, S., Yamamura, T., Berberich, I., Cardell, S., Kronenberg, M., and Herrmann, T. (2006) The
complementarity determining region 2 of BV8S2 (V beta 8.2) contributes to antigen recognition by rat invariant NKT cell
TCR. J Immunol 176: 7447-7455
Reichardt, H.M., Gold, R., and Lühder, F. (2006) Glucocorticoids in multiple sclerosis and experimental autoimmune
encephalomyelitis. Expert Rev Neurotherapeutics 6: in press.
Rincon-Orozco, B., Kunzmann, V., Wrobel, P., Kabelitz, D., Steinle, A., Herrmann, T. (2005) Activation of V gamma 9V delta 2 T
cells by NKG2D.J Immunol. 175: 2144-51.
Rodríguez-Palmero, M., À. Franch, M. Castell, C. Pelegrí, F.J. Pérez-Cano, C. Kleinschnitz, G. Stoll, T. Hünig, and C. Castellote
(2006). Effective Treatment of Adjuvant Arthritis with a stimulatory CD28-specific monoclonal antibody. The Journal of
Rheumatology 2006; 33(1):110-8
Tischner D, Weishaupt A, van den Brandt J, Müller N, Beyersdorf N, Ip CW, Toyka KV, Hünig T, Gold R, Kerkau T, Reichardt HM
(2006) Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of Multiple Sclerosis.
Brain 129:2635-2647.
Tuckermann, J.P., Kleiman, A., McPherson, K.G., and Reichardt, H.M. (2005) Molecular mechanisms of glucocorticoids in the
control of inflammation and lymphocyte apoptosis. Crit Rev Clin Lab Sci 42: 71-104.
van den Brandt, J., Kwon, S.H., Hünig, T., McPherson, K.G., and Reichardt, H.M. (2005). Sustained preTCR expression in
Notch1IC transgenic rats impairs T cell maturation and selection. Journal of Immunology 174: 7845-7852.
van den Brandt, J., Kwon, S.H., McPherson, K.G., Petrovic, S., Zettl, A., Müller-Hermelink, H.K., and Reichardt, H.M. (2006)
Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats. Eur J Immunol 36: 2223-2234.
Verschelde, C., Michonneau, D., Trescol-Biemont, M. C., Berberich, I., Schimpl, A., and Bonnefoy-Berard, N. (2006)
Overexpression of the antiapoptotic protein A1 promotes the survival of double positive thymocytes awaiting positive
selection. Cell Death Differ 13: 1213-1221
Voigt, H., Schrama, D., Eggert, A.O., Vetter, C.S., Müller-Blech, K., Reichardt, H.M., Andersen, M.H., Becker, J.C., and Lühder, F.
(2006) CD28-mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin
Exp Immunol 143: 93-102.
Wang, D., Müller, N., McPherson, K.G., and Reichardt, H.M. (2006) Glucocorticoids engage different signal transduction
pathways to induce apoptosis in thymocytes and mature T cells. J Immunol 176: 1695-1702.
3-3 Institute of Hygiene and Microbiology:
Abele-Horn, M., Vogel, U., Klare, I., Konstabel, C., Trabold, R., Kurihara, R., Witte, W., Kreth, W., Schlegel, P.G., and Claus, H.
Molecular epidemiology of hospital-acquired vancomycin-resistant enterococci. J Clin Microbiol in press
Abele-Horn, M., Stoy, K., Frosch, M. and reinert, R.R. (2006) Comparative evaluation of a new Vitek 2 system for identification
and antimicrobial susceptibility testing of Streptococcus pneumoniae. Eur. J. Clin. Microbiol. Infect. Dis. 25: 55-57.
Abele-Horn, M., Hommers, L., Trabold, R. and frosch, M. (2006) Validation of VITEK 2 version 4.01 software for detection,
identification, and classification of glycopeptide-resistant enterococci. J. Clin. Microbiol. 44: 71-76.
Aires-de-Sousa, M., 18 other authors, Vogel, U., Westh, H., Xu, J. and Witte, W. (2006). High Inter-laboratory Reproducibility of
DNA Sequence-Based Typing of Bacteria in a Multicenter Study. J Clin Microbiol 44: 619-621.
Berg, T., Schild, S., and Reidl, J. (2006) Characterisation of the regulation of the chitosan-phospho-transferase system in
Vibrio cholerae. Microbiol, in press.
Brehm, K., Spiliotis, M., Zavala-Gongora, R., Konrad, C., and Frosch, M. (2006) The molecular mechanisms of larval cestode
development: first steps into an unknown world. Parasitol Int 55: S15-S21.
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Claus, H., Harmsen, D., and Vogel, U. (2005). DNA-sequence based tandem repeat analysis of the clfB gene is less
discriminatory than spa-typing for methicillin-resistant Staphylococcus aureus. Intern J Med Microbiol 294:525-528.
Claus, H., Maiden, M.C.J., Wilson, D.J., McCarthy, N.D., Jolley, K.A., Urwin, R., Hessler, F., Frosch, M. and Vogel, U. (2005).
Genetic analysis of meningococci carried by children and young adults. J Infect Dis 191:1263-1271.
Claus, H., Vogel, U., Swiderek, S., Frosch, M., and Schoen, S. 2006. Microarray analyses of meningococcal genome composition
and gene regulation: review of the recent literature. In revision FEMS Microbiol. Rev., in press.
Elias, J. and Vogel, U. IS1301 fingerprint analysis of Neisseria meningitidis strains belonging to the ET-15 clone. J Clin
Microbiol, in press.
Elias, J., Frosch, M., and Vogel, U. 2006. Meningokokkeninfektionen in Deutschland 2005: Daten des Nationalen Referenzzentrums. ImpfDialog 3:119-124.
Elias, J., Harmsen, D., Claus, H., Hellenbrand, W., Frosch, M., and Vogel, U. 2006. Spatio-temporal analysis of meningococcal
disease in Germany. Emerg Infect Dis 12:1689-1695.
Elias, J., Health Office in the Rural District Office Wartburgkreis, Claus, H., Frosch, M., and Vogel, U. Evidence for indirect
nosocomial transmission of Neisseria meningitidis resulting in two cases of invasive meningococcal disease. J Clin
Microbiol in press
Findlow, H., Vogel, U., Mueller, J.E., Curry, A., Njanpop-Lafourcade, B.M., Claus, H., Gray, S.J., Yaro, S., Traoré, Y., Sangaré, L.,
Nicolas, P., Gessner, B.D., and Borrow, R. Three cases of invasive meningococcal disease in Burkina Faso caused by a
capsule null locus strain circulating among healthy carriers. J. Infect. Dis., in press.
Fox, A.J., Taha, M.K., and Vogel, U. Standardized non-culture techniques recommended for European reference laboratories.
FEMS Microbiol. Rev., in press.
Frosch, M. and Maiden, M. The European networking for combating meningococcal disease. FEMS Microbiol. Rev., in press.
Frosch, M. and Vogel, U. (2006) Structure and genetics of the meningococcal capsule. In: Handbook of Meningococcal
Disease. Ed.: Frosch, M. Maiden, M.C.J. 1st. edition. Wiley-VCH, Weinheim.
Geiger, D., Debus, E.S., Ziegler, U.E., Larena-Avellaneda, A., Frosch, M., Thiede, A. and Dietz, U.A. (2005) Capillary activity of
surgical sutures and suture-dependent bacterial transport: a qualitative study. Surg. Infect. 6: 377-383.
Gelmedin, V., Zavala-Gongora, R., Fernandez, C., and Brehm, K. (2005) Echinococcus multilocularis: cloning and
characterization of a member of the SNW/SKIP family of transcriptional coregulators. Exp Parasitol 111: 115-120.
Gerlach, G., and Reidl, J. (2006) NAD-Pathway in Pasteurellaceae: Simplification of a complex pathway. J Bacteriol 188:67196727.
Hautmann, W., Harms, I., Vogel, U., Zirngibl, A., and Wildner, M. (2005). Cluster von Meningokokkenerkrankungen im Allgäu –
Interventionsstrategien. Gesundheitswesen. 67: 853-857.
Heldwein, K., Biedermann, H.G., Hamperl, W.D., Bretzel, G., Loscher, T., Laregina, D., Frosch, M., Buttner, D.W. and Tappe, D.
(2006) Subcutaneous Taenia crassiceps infection in a patient with non-Hodgkin’s lymphoma. Am. J. Trop. Med. Hyg. 75:
108-111.
Jarva, H, Ram, S., Vogel, U., Blom, A.M. and Meri, S. (2005) Binding of the complement inhibitor C4bp to serogroup B Neisseria
meningitidis. J Immunol 174(10):6299-6307.
Jung, S., Zimmer, S., Lueneberg, E., Frosch, M., Karch, H., Korn, T. and Toyka, K.V. (2005) Lipooligosaccharide of campylobacter
jejuni prevents myelin-specific enteral tolerance to autoimmune neuritis – a potential mechanism in Guillain-Barre
syndrome. Neurosci. Lett. 381: 175-178.
Khayath, N., Vicogne, J., Ahier, A., Ben Younes, A., Konrad, C., Trolet, J., Viscogliosi, E., Brehm, K. and Dissous, C. (2006)
Diversification of the insulin receptor family in the helminth parasite Schistosoma mansoni. FEBS J., in press.
Kurzai O., Schmitt, C., Claus, H., Vogel, U., Frosch, M, Kolb-Maurer, A. (2005) Carbohydrate composition of meningococcal
lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell Microbiol 7:131934.
Kurzai, O., Frosch, M. (2006) Cellular immune responses in meningococcal disease. In: Frosch, M., Maiden, M. (eds.)
Handbook of Meningococcal Disease, Wiley-VCH, Weinheim, Germany.
Kurzai, O., Schmitt, C., Bröcker, E., Frosch, M., Kolb-Mäurer, A. (2006) Polymorphism of Candida albicans is a major factor in
the interaction with human dendritic cells. Int J Med Microbiol 295:121-127.
Kurzai, O., Schmitt, C., Claus, H., Vogel, U., Frosch, M., Kolb-Mäurer, A. (2005) Carbohydrate composition of meningococcal
lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell Microbiol 7:13191334.
Lappann, M., Haagensen, J.A.J., Claus, H., Vogel, U., and Molin, S. Meningococcal biofilm formation: Structure, development,
and phenotypes in a standardized continuous flow system. Mol Microbiol in press.
Madico, G., Welsch, J.A., Lewis, L.A., McNaughton, A., Perlman, D.H., Costello, C.E., Ngampasutadol, J., Vogel, U., Granoff,
D.M., Ram, S. (2006) The Meningococcal Vaccine Candidate GNA1870 Binds the Complement Regulatory Protein Factor
H and Enhances Serum Resistance. J Immunol 177:501-10.
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101
Merdanovic, M., Sauer, S., and Reidl, J. (2005) Coupling of NAD+ biosynthesis and nicotinamide ribosyl transport: Characterization
of NadR ribonucleotide-kinase mutants of Haemohilus influenzae. J Bacteriol 187:4410-4420.
Müller, I., Brade, V., Hagedorn, H.J., Straube, E., Schörner, C., Frosch, M., Hlobil, H., Stanek, G. and Hunfeld, K.P. (2006) Is
serological testing a reliable tool in laboratory diagnosis of syphilis? Meta-analysis of eight external quality control
surveys performed by the german infection serology proficiency testing program. J. Clin. Microbiol. 44: 1335-1341.
Nikulin, J., Panzner, U., Frosch, M. and Schubert-Unkmeir, A. (2006) Intracellular survival and replication of Neisseria meningitidis
in human brain microvascular endothelial cells. Int J Med Microbiol. 296: 553-558.
Oppermann, H., Thriene, B., Irmscher, H.M., Gräfe, L., Borrmann, M., Bellstedt, D., Kaynak, S., Hellenbrand, W., und Vogel, U.
Meningokokken-Trägerstatus von Gymnasiasten und mögliche Risikofaktoren. Gesundheitswesen. in press.
Ram, S. and Vogel, U. (2006) Role of Complement in Defense Against Meningococcal Infection. In: Handbook of Meningococcal
Disease. Ed.: Frosch, M. Maiden, M.C.J. 1st. edition. Wiley-VCH, Weinheim.
Schild, S., Lamprecht, A.-K., and Reidl, J. (2005) Functional characterization of surface polymer:lipid A-core ligases of Vibrio
cholerae. J Biol Chem 280: 25936-25947.
Schild, S., Lamprecht, A.-K., Fourestier, C., Lauriano C.M., Klose, K.E., and Reidl, J. (2005) Characterizing LPS and core lipid
A mutant O1 and O139 Vibrio cholerae strains for adherence properties on mucus producing cell line HT-29-Rev MTX
and virulence in mice. Int J Med Microbiol 295:243-251.
Schoen, C., Claus, H., Vogel, U., and Frosch, M. (2006) The genomes of pathogenic Neissera species. In: Pathogenomics,
edited by J. Hacker and U. Dobrindt, Weinheim:Wiley-VCH, 2006, p. 231-255.
Schoen C. and H. Claus (2006) Neisseria meningitidis genome sequencing projects. In: Frosch M, Maiden MC, eds.
Meningococcal Disease: Pathogenicity and Prevention. Weinheim: Wiley-VCH; pp. 77-97.
Schrauder, A., Claus, H., Elias, J., Vogel, U., Haas, W., and Hellenbrand, W. Capture-Recapture Analysis to estimate the
Incidence of Invasive Meningococcal Disease in Germany, 2003. Epidemiol Infect in press
Schröter, M., Elias, J., Hellenbrand, W., Ziemer, B., Baumeister, H., and Vogel, U. 2006. Die Epidemiologie von Neisseria
meningitidis in NRW. Rheinisches Ärzteblatt 4: 19-21.
Schubert-Unkmeir A., A. Schramm-Glück, M. Frosch and C. Schoen. Transcriptome analyses in the interaction of Neisseria
meningitidis with mammalian host cells. Methods Mol Biol in press.
Schubert-Unkmeir, A., Sokolova, O., Panzner, U., Egenthaler, M. and Frosch, M. Gene expression pattern in human brain
endothelial cells in response to Neisseria meningitidis. Infect. Immun., in press.
Siauw, C., Kobsar, A., Dornieden C, Beyrich C, Schinke B, Schubert-Unkmeir, A., Abele-Horn, M., Speer, C., Eigenthaler, M.
(2006) Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signalling
cascades. Thromb Haemost. 95: 836-849.
Spiliotis, M., Konrad, C., Gelmedin, V., Tappe, D., Brückner, S., Mösch, H.U., and Brehm, K. (2006) Characterisation of EmMPK1,
an ERK-like MAP kinase from Echinococcus multilocularis which is activated in response to human epidermal growth
factor. Int J Parasitol 36: 1097-1112.
Spiliotis, M., Tappe, D., Brückner, S., Mösch, H.U., and Brehm, K. (2005) Molecular cloning and characterization of Ras- and
Raf-homologues from the fox-tapeworm Echinococcus multilocularis. Mol Biochem Parasitol 193: 225-237.
Stummeyer, K., Schwarzer, D., Claus, H., Vogel, U., Gerardy-Schahn, R., and Mühlenhoff, M. 2006. Evolution of bacteriophages
infecting encapsulated bacteria: lessons from Escherichia coli K1-specific phages. Mol Microbiol 60:1123-35.
Swiderek, H., Claus, H., Frosch, M., and Vogel, U. (2005). Evaluation of custom-made DNA microarrays for multilocus sequence
typing of Neisseria meningitidis. Intern J Med Microbiol 295:39-45.
Taha, M.-K., Alonso, J.-M., Clarke, S.C., Caugant, D.A., Diggle, M.A., Fox, A., Frosch, M., Gray, S.J., Guiver, M., Heuberger, S.,
Cafferkey, M., Kalmusova, J., Klem, A., Kriz, P., Kesanopoulos, K., Marsh, J., Mölling, P., Murphy, K., Olcén, P., Sanou, O.,
Tzanakaki, G., and Vogel, U. (2005) Interlaboratory comparison of PCR-based identification and genogrouping of Neisseria
meningitidis. J Clin Microbiol 43:144-149.
Tappe, D., Winzer, R., Büttner, D.W., Strobel, P., Stich, A., Klinker, H. and Frosch, M. (2006) Linguatuliasis in Germany. Emerg.
Inf. Dis. 12: 1034-1036.
Tappe, D., Dirks, J., Müller, R., Brederlau, J., Abele-Horn, M., Suerbaum, S., Kurzai, O. (2005) Fatal Clostridium tertium
septicemia in a nonneutropenic patient. J Infect 50:76-80.
Tappe, D., Claus, H., Kern, J., Marzinzig, A., Frosch, M. and Abele-Horn, M. (2006) First case of febrile bacteremia due to a wildtype and small-colony variant of Escherichia coli. Eur. J. Clin. Microbiol. Infect. Dis. 25: 31-34.
Trotter, C.L., Chandra, M., Cano, R., Larrauri, A., Ramsay, M.E., Brehony, C., Jolley, K.A., Maiden, M.C., Heuberger, S. and
Frosch, M. A surveillance network for meningococcal disease in Europe. FEMS Microbiol. Rev., in press.
Valenza, G., Burgemeister, S., Girschick, H., Schoen, C., Veihelmann, S., Moter, A., Haban, V., Vogel, U., and Schlagenhauf, U.
2006. Analysis of the periodontal microbiota in childhood-type hypophosphatasia. Int J Med Microbiol 296:493-500.
Valenza, G., Kallmann, B., Berend, A., Mlynski, R., Nöckler, K., Kurzai, O., Frosch, M., Abele-Horn, M. (2006) Isolation of Brucella
melitensis from a patient with hearing loss. Eur J Clin Microbiol Infect Dis 25:67-68.
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Valenza, G., Valenza, R., Brederlau, J., Frosch, M., Kurzai, O. (2006) Identification of Candida fabianii as a cause of lethal
septicaemia. Mycoses 49:331-334.
Vehreschild, J.J., Krüger, K., Kurzai, O., Wickenhauser, C., Behringer, K., Tox, U., Cornely, O.A. (2006) Salvage therapy of
refractory chronic disseminated candidiasis in a patient with acute myeloid leukaemia and secondary prophylaxis during
allogeneic stem cell transplantation. Mycoses 49:42-47.
Vogel, U., Elias, J., and Frosch, M. (2005). Epidemiologie der Meningokokkeninfektion aus Sicht des Nationalen Referenzzentrums für Meningokokken. Impfdialog 3:117-121.
Vogel, U., Kurzai, O., Claus, H., Knaust, A., and Pitten, F.-A.. (2005) Spa-Typisierung von Methicillin-resistenten Staphylococcus
aureus Stämmen am Universitätsklinikum Würzburg. Der Mikrobiologe. 15:131-135.
Weber, M.V.R., Claus, H., Maiden, M.C.J., Frosch, M., and Vogel, U. (2006) Genetic mechanisms for loss of encapsulation in
polysialyltransferase-gene-positive meningococci isolated from healthy carriers. Int J Med Microbiol 296:475-84.
Zavala-Gongora, R., Kroner, A., Bernthaler, P., Knaus, P., and Brehm, K. (2006) A member of the transforming growth factor-b
receptor family of Echinococcus multilocularis is activated by human bone morphogenetic protein 2. Mol Biochem Parasitol
146: 265-271.
3-4 Chair of Microbiology:
Armstrong, S.K., and Gross, R. (2006) Metabolism and physiology of Bordetella species. In: Molecular Biology of Bordetella.
Ed.: Locht, C. Horizon Scientific Press, Norfolk, U.K., in press.
Beier, D., and Gross, R. (2006) Regulation of bacterial virulence by two-component systems. Curr Opin Microbiol 9: 1-10.
Beier, D., and Gross, R. (2006) The Bordetella virulence regulon controlled by the BvgAS two-component system. In: Bacterial
Signal Transduction: Regulatory Networks and Drug Targeting. Ed.: Utsumi, R. Landes Bioscience, Georgetown USA, in
press.
Dominguez-Bernal, G., Müller-Altrock, S., Gonzalez-Zorn, B., Scortti, M., Herrmann, P., Monzo, H.J., Lacharme, L., Kreft J., and
Vazquez-Boland, J.-A. (2006) A spontaneous genomic deletion in Listeria ivanovii identifies LIPI-2, a species-specific
pathogenicity island encoding sphingomyelinase and numerous internalins. Mol Microbiol 59:415-432.
Eisenreich, W., Slaghuis, J., Lauptiz, R., Bussemer, J., Stritzker, J., Schwarz, C., Schwarz, R., Dandekar, T., Goebel , W. and
Bacher, A. (2006) 13C isotopolouge perturbation studies of Listeria monocytogenes carbon metabolism and its modulation
by the virulence regulator PrfA. Proc Natl Acad Sci USA 103: 21040-2045.
Feldhaar, H., Zientz, E., and Gross, R. (2006) Metabolic interactions between the carpenter ant Camponotus floridanus and its
endosymbiont Blochmannia. Nova Acta Leopoldina, in press.
Gaudermann, P., Vogl, I., Zientz, E., Silva, F., Moya, A., Gross, R., and Dandekar, T. (2006) Function predictions for conserved
hypothetical proteins and proteins with putative function in Blochmannia floridanus. BMC Microbiol 6:1-15.
Gentschev, I., Fensterle, J., Schmidt, A., Potapenko ,T., Troppmair, J, Goebel , W., Rapp, U.R. (2005) Use of a recombinant
Salmonella enterica serovar Typhimurium strain expressing C-Raf for protection agains C-Raf induced lung adenoma in
mice. BMC Cancer 9:15.
Goebel, W. and Lory, S. (2006) Prokaryotic cell regulation Curr Opin Microbiol 9:123-126.
Gopal, S., Borovok, I., Ofer, A., Yanku, M., Cohen, G., Goebel, W., Kreft, J., and Aharonowitz, Y. (2005) A multidomain fusion
protein in Listeria monocytogenes catalyzes the two primary activities for glutathione biosynthesis. J Bacteriol 187:38393847.
Gottschalk, G., Goebel, W. and Pühler, A. (2006) Aspects of prokaryotic genome research. J Biotechnol 126: 1-2.
Gross, R., Zientz, E., and Feldhaar, H. (2006) Intrazelluläre bakterielle Endosymbiosen in Insekten. BioSpektrum 12: 23-25.
Hain, T., Steinweg, C., Kuenne, C.T., Billion, A., Ghai, R., Chatterjee, S.S., Domann, E., Kärst, U., Goesmann, A., Bekel, T.,
Bartels, D., Kaiser, O., Meyer, F., Pühler, A., Weisshaar, B., Wehland, J., Liang, C., Dandekar, T., Lampidis, R., Kreft, J.,
Goebel, W., and Chakraborty, T. (2006) Whole-genome sequence of Listeria welshimeri reveals common steps in genome
reduction with Listeria innocua as compared to Listeria monocytogenes. J Bacteriol 188:7405-7415.
Horvat, A., and Gross, R. (2006) Molecular characterisation of the BvgA response regulator of Bordetella holmesii. Microbiol
Res, in press.
Jiménez-Pearson, M.-A., Delany, I., Scarlato, V., and Beier, D. (2005) Phosphate flow in the chemotactic response system of
Helicobacter pylori. Microbiology 151: 3299-3311.
Jiménez-Pearson, M.-A., Dietz, P., and Beier, D. (2005) Protein-protein interaction of HP137 with histidine kinase HP244 does
not contribute to flagellar regulation in Helicobacter pylori. Microbiol Res 166: 299-305.
Joseph, B., and Beier, D. (2006) Global analysis of two-component gene regulation in Helicobacter pylori by mutation
analysis and transcriptional profiling. Methods Enzymol, in press.
Joseph, B., Przybilla, K., Stuhler, C., Schauer, K., Slaghuis ,J., Fuchs, T.M. and Goebel, W. (2006) Identifcation of Listeria
monocytgenes genes contributing to intracellular regplation by expression profiling and mutant screening. J Bacteriol
188: 556-568.
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Löffler, D.I , Schoen, C.,U. Goebel, W. and Pilgrim S. (2006) Comparison of different live vaccine strategies in vivo for delivery
of protein antigen or antigen-encoding DNA and mRNA by virulence-attenuated Listeria monocytogenes. Infect Immun
74: 3946-3957.
Luo, Q., Herler, M., Müller-Altrock, S. and Goebel, W. (2005) Supportive and inhibitory elements for a putative PrfA-dependent
promoter in Listeria mónocytogenes. Mol Microbiol 55: 986-997.
Marr, A.K., Joseph, B., Mertins, S., Ecke, R., Müller-Altrock, S. and Goebel, W. (2006) Overexpression of PrfA leads to growth
inhibition of Listeria monocytogenes in glucose-containing culture media by interfering with glucose uptake. J Bacteriol
188: 3887-3901.
Mauder, N., Ecke, R., Mertins, S., Loeffler, D.I., Seidel, G., Sprehe, M., Hillen, W., Goebel, W. and Müller-Altrock S. (2006)
Species-specific differences in the activity of PrfA, the key regulator of listerial virulence genes. J Bacteriol [Epub ahead of
print]
Middendorf, B., Stübs, D., Guiso, N., Deppisch, H., Gross, R., and Fuchs, T.M. (2005) Phg, a novel member of the autotransporter
family present in Bordetella species. Microbiol Res 160: 329-336.
Müller, S., Förster, J., and Beier, D. (2006) Repeated sequence motifs in the Helicobacter pylori P1408 promoter do not affect its
transcription. Microbiol Res 161: 212-221.
Müller, S., Pflock, M., Schär, J., Kennard, S., and Beier, D. (2006) Regulation of expression of atypical orphan response
regulators of Helicobacter pylori. Microbiol Res, in press.
Pflock, M., Finsterer, N., Joseph, B., Mollenkopf, H., Meyer, T.F., and Beier, D. (2006) Characterization of the ArsRS regulon of
Helicobacter pylori involved in acid adaptation. J Bacteriol 188: 3449-3462.
Pflock, M., Kennard, S., Delany, I., Scarlato, V., and Beier, D. (2005) Acid-induced activation of the urease promoters is
mediated directly by the ArsRS two-component system of Helicobacter pylori. Infect Immun 73: 6437-6445.
Pflock, M., Kennard, S., Finsterer, N., and Beier, D. (2006) Acid-responsive gene regulation in the human pathogen Helicobacter
pylori. J Biotechnol 126: 52-60.
Rauch, M., Luo, Q., Müller-Altrock, S., and Goebel, W. (2005) SigB-dependent in vitro transcription of prfA and some newly
identified genes of Listeria monocytogenes whose expression is affected by PrfA in vivo. J Bacteriol 187: 800-804.
Schär, J., Sickmann, A., and Beier, D. (2005) Phosphorylation-independent activity of atypical response regulators of Helicobacter
pylori. J Bacteriol 187: 3100-3109.
Schmaußer, B., Endrich, S., Brändlein, S., Schär, J., Beier, D., Müller-Hermelink, H.-K., and Eck, M. (2005) The chemokine
receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, H. pylori gastritis, gastric carcinoma and its
precursor lesions and upregulated by H. pylori. Clin Exp Immunol 139: 323-327.
Schmid, M.W., Ng, E.Y., Lampidis, R., Emmerth, M., Walcher, M., Kreft, J., Goebel, W., Wagner, M., and Schleifer, K.H. (2005)
Evolutionary history of the genus Listeria and its virulence genes. Syst Appl Microbiol 28:1-18.
Schoen, C., Kolb-Mäurer, A., Geginat, G., Löffler, D., Bergmann, B., Stritzker, J., Szalay, A.A., Pilgrim, S. and Goebel, W. (2005)
Bacterial delivery of functional messenger RNA to mammalian cells. Cell Microbiol 7: 709-724.
Stoll, S., Gadau, J., Gross, R., and Feldhaar, H. (2006) Comparative phylogenetic diversity of the bacterial community associated
with ants of the genus Tetraponera. Biol. J. Lin. Soc., in press.
Stritzker, J., Schoen, C. and Goebel, W. (2005) Enhanced synthesis of internalin A in aro mutants of Listeria monocytogenes
indicates posttranscriptional control of the inlAB mRNA. J Bacteriol 187: 2836-2845.
Stübs, D., Fuchs, T.M., Schneider, B., Bosserhoff, A., and Gross, R. (2005) Identification and regulation of cold inducible factors
of Bordetella bronchiseptica. Microbiology 151: 1895-1909.
Williams, T., Bauer, S., Beier, D., and Kuhn, M. (2005) Construction and characterization of Listeria monocytogenes mutants
with in-frame deletions in the response regulator genes identified in the genome sequence. Infect Immun 73: 31523159.
Williams, T., Joseph, B., Beier, D., Goebel, W., and Kuhn, M. (2005) Response regulator DegU of Listeria monocytogenes
regulates the expression of flagella-specific genes. FEMS Microbiol Lett 252: 287-298.
Zientz, E., Beyaert, I., Gross, R. and Feldhaar, H. (2006) Relevance of the endosymbiosis of Blochmannia floridanus and
carpenter ants at different stages of the life cycle of the host. Appl Env Microbiol 72: 6027-6033.
Zientz, E., Feldhaar, H., Stoll, S., and Gross, R. (2005) Insights into the microbial world associated with ants. Arch Microbiol
184:199-206.
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3-5 Institute of Molecular Infection Biology:
Agerer, F., S. Lux, A. Michel, M. Rohde, K. Ohlsen, and C. R. Hauck. (2006) Cellular invasion by Staphylococcus aureus reveals
a functional link between focal adhesion kinase and cortactin in integrin-mediated internalisation. J. Cell Sci. 118:21892200.
Albert C, Jacobi S, De Buck E, Lammertyn E, Heuner K. (2006) Identification of target proteins of the Lss secretion system of
Legionella pneumophila Corby. In Legionella: State of the art 30 years after its recognition, N.P.Cianciotto, Y.Abu Kwaik,
P.H.Edelstein, B.S.Fields, D.F.Geary, T.G.Harrison, C.A.Joseph, R.M.Ratcliff, J.E.Stout, and M.S.Swanson, eds. (Washington, D.C.: ASM Press), pp. 221-223.
Alpert, C., Engst, W., Gühler, A., Oelschlaeger, T.A., and Blaut, M. (2005) Bacterial response to eukaryotic cells: analysis of
differentially expressed proteins using nano liquid chromatography-electrospray ionization tandem mass spectrometry.
J Chromatography 1082: 25-32.
Appeldoorn, C.C.M., Joosten, J.A.F., Ait el Maate, F., Dobrindt, U., Hacker, J., Liskamp, R.M.J., Khan, A.S., Pieters, R.J. (2005)
Novel multivalent mannose compounds and their inhibition of the adhesion of type 1 fimbriated uropathogenic E. coli.
Tetrahedron: Asymmetry 16:361-372.
Bader, T., Schröppel, K., Bentink, S., Agabian, N., Köhler, G., and Morschhäuser, J. (2006) Role of calcineurin in stress resistance,
morphogenesis, and virulence of a Candida albicans wild-type strain. Infect Immun 74: 4366-4369.
Batzilla CF, Rachid S, Engelmann S, Hecker M, Hacker J, Ziebuhr W. (2006) Impact of the accessory gene regulatory system
(Agr) on extracellular proteins, codY expression and amino acid metabolism in Staphylococcus epidermidis.Proteomics.
Jun;6(12):3602-13.
Beloin, C., Michaelis, K., Lindner, K., Landani, P., Hacker, J., Ghigo, J.M., Dobrindt, U. (2006) The transcriptional antiterminator
RfaH rpresses biofilm formation in Escherichia coli. J. Bacteriol., 188,1316 – 1331.
Biswas, K., and Morschhäuser, J. (2005) The Mep2p ammonium permease controls nitrogen starvation-induced filamentous
growth in Candida albicans. Mol Microbiol 56: 649-669.
Blumer, C., Kleefeld, A., Lehnen, D., Heintz, M., Dobrindt, U., Nagy, G., Michaelis, K., Emödy, L., Polen, T., Rachel, R., Wendisch,
V., Unden, G. (2005) Regulation of type 1 fimbriae synthesis and biofilm formation by the transcriptional regulator LrhA of
Escherichia coli. Microbiology 151: 3287-3298.
Braun, B.R., van het Hoog, M., d’Enfert, C., Martchenko, M., Dungan, J., Kuo, A., Inglis, D.O., Uhl, M.A., Hogues, H., Berriman, M.,
Lorenz, M., Levitin, A., Oberholzer, U., Bachewitch, C., Harcus, D., Marcil, A., Dignard, D., Iouk, T., Zito, R., Frangeul, L.,
Tekaia, F., Rutherford, K., Wang, E., Munro, C.A., Bates, S., Gow, N.A., Hoyer, L., Köhler, G., Morschhäuser, J., Newport, G.,
Znaidi, S., Raymond, M., Turcotte, B., Sherlock, G., Costanzo, M., Ihmels, J., Berman, J., Sanglard, D., Agabian, N.,
Mitchell, A.P., Johnson, A.D., Whiteway, M., and Nantel, A. (2005) A human-curated annotation of the Candida albicans
genome. PloS Genetics 1: 36-57.
Bringmann, G., I. Kajahn, M. Reichert, S. E. H. Pedersen, J. H. Faber, T. Gulder, R. Brun, S. B. Christensen, A. Ponte-Sucre, H.
Moll, G. Heubl and V. Mudogo (2007). Ancistrocladinium A and B, the First N,C-Coupled Naphthyldihydroisoquinoline
Alkaloids, from a Congolese Ancistrocladus Species. J. Org. Chem. (in press).
Brüggemann H, Hagman A, Jules M, Sismeiro O, Dillies M-A, Gouyette C, Kunst F, Steinert M, Heuner K, Coppée J-Y,
Buchrieser C. (2006) Virulence strategies for infecting phagocytes deduced from the transcriptional program of Legionella
pneumophila. Cell. Microbiol. 8:1228-1240.
Brzuszkiewics, E., Brüggemann, H., Liesegang, H., Emmerth, M., Ölschläger, T., Nagy, G., Albermann, K., Wagner, C., Buchrieser,
C., Emödy, L., Gottschalk, G., Hacker, J. and Dobrindt, U. (2006) How to become a uropathogen: Comparative genomic
analysis of extraintestinal pathogenic Escherichia coli strains. Proc Natl Acad Sci USA 103: 12879-12884.
Coste, A., Turner, V., Ischer, F., Morschhäuser, J., Forche, A., Selmecki, A., Berman, J., Bille, J., and Sanglard, D. (2006) A
mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome
5 to mediate antifungal resistance in Candida albicans. Genetics 172: 2139-2156.
Dobrindt, U. (2005). (Patho-)Genomics of E. coli. Int. J. Med. Microbiol. 295:357-371.
Dobrindt, U., Hacker, J. (2005) (Patho-)Genomics of Escherichia coli and Shigella. In: Pathogenomics (J. Hacker, U. Dobrindt,
eds.) Wiley-VCH, Weinsheim, 85-108.
Dobrindt, U., Hacker, J. (2005) Plasmids, Phages and Pathogenicity islands in relation with bacterial protein toxins: Impact on
the evolution of microbes. In: Bacterial protein toxins: A sourcebook, 3. Edition (J. Alouf, M. Popoff, eds.), Elsevier Ltd.
Engel, D., Dobrindt, U., Tittel, A., Peters, P., Maurer, J., Gütgermann, I., Kaissling, B., Kuziel, W., Jung, S., and Kurts, C. (2006)
TNF{alpha}/iNOS-producing dendritic cells are rapidly recruited to the bladder in urinary tract infection, but are dispensable
for bacterial clearance. Infect. Immun. 74: 6100-6107.
Farbrother, P., Wagner, C., Na, J., Tunggal, B., Morio, T., Urshihara, H., Tanaka, Y., Schleicher, M., Steinert, M., Eichinger, L.
(2006) Dictyostelium transcriptional host cell response upon infection with Legionella. Cell. Microbiol. 8. 438-56.
Gaur, N.A., Manoharlal, R., Saini, P., Prasad, T., Mukhopadhyay, G., Hoefer, M, Morschhäuser, J., and Prasad, R. (2005) Ex-
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pression of the CDR1 efflux pump in clinical Candida albicans isolates is controlled by a negative regulatory element.
Biochem Biophys Res Commun 332: 206-214.
Germon, P., Roche, D., Melo, S., Mignon-Grasteau, S., Dobrindt, U., Hacker, J., Schouler, C., Moulin-Schouleur, M. (2006)
Relationships between phylogenetic groups, ecto-chromosomal DNA insertion hot-spots and the integrity of tDNA loci in
the genome of Escherichia coli strains. Microbiology, accepted for publication.
Hacker, J. (2006) Warum Bakterien krank machen – Zur Molekularbiologie bakterieller Pathogenitätsmechanismen. Nordrhein-Westfälische Akademie der Wissenschaften, Vorträge, Reihe N, 471, 1 – 36.
Hacker, J., Dobrindt, U., Gottschalk, G., Brüggemann, H., Carniel, E., Buchrieser, C., Middendorf, B., B. Hochhut, B. (2005).
Analysis of Infectious Agents and the Concept of Pathogenicity Islands. Nova Acta Leopoldina 344:61-65.
Hacker, J., Dobrindt, U., Steinert, M., Merkert, H., Hentschel, U. (2005) Co-evolution of bacteria and their hosts: A marriage
made in heaven or hell? In: The Influence of cooperative bacteria on their animal host biology (M. J. McFall-Ngai, B.
Henderson, E. G. Ruby, eds.), Cambridge University Press, Cambridge, 57-72.
Hammerschmidt, S., Hacker, J., Klenk, H.D. (2005) Threat of Infection: Microbes of high pathogenic potential strategies of
detection, control and eradication. Int. J. Med. Microbiol. 295, 141 – 151.
Harraghy, N., J. Kormanec, C. Wolz, D. Homerova, C. Goerke, K. Ohlsen, S. Qazi, P. Hill, and M. Herrmann. (2006) sae is
essential for expression of the staphylococcal adhesins Eap and Emp. Microbiology 151:1789-1800.
Hauck, C. R., and K. Ohlsen. (2006) Sticky connections: extracellular matrix protein recognition and integrin-mediated cellular
invasion by Staphylococcus aureus. Curr. Opin. Microbiol. 9:1-7.
Hechard, Y., Ferraz, S., Bruneteau, E., Steinert, M., Berjeaud, J.-M. (2005) Isolation and characterization of a Staphylococcus
warneri strain producing an anti-Legionella peptide. FEMS Microbiol. Lett. 252: 19-23.
Hejnova, J., Dobrindt, U., Nemcova, R., Rusniok, C., Bomba, A., Frangeul, L., Hacker, J., Glaser, P., Buchrieser, C., Šebo, P.
(2005) Characterization of the flexible genome complement of the probiotic Escherichia coli strain A0 34/86 (O83:K24:H31).
Microbiology 151: 385-398.
Hentschel, U., Ölschläger, T., Dobrindt, U., Hacker, J. (2005) Mechanisms of Destruction and Healing in Ecosystems: A
Microbiologist’s View. Nova Acta Leopoldina, 343, 121 – 126.
Heuner K, Jacobi S, Albert C, Steinert M, Brüggemann H, Buchrieser C. (2006). Gene Expression and Virulence in Legionella:
The Flagellar Regulon. In Legionella: State of the art 30 years after its recognition, N.P.Cianciotto, Y.Abu Kwaik, P.H.Edelstein,
B.S.Fields, D.F.Geary, T.G.Harrison, C.A.Joseph, R.M.Ratcliff, J.E.Stout, and M.S.Swanson, eds. (Washington, D.C.: ASM
Press), pp. 327-332.
Hiller, D., Sanglard, D., and Morschhäuser, J. (2006) Overexpression of the MDR1 gene is sufficient to confer increased
resistance to toxic compounds in Candida albicans. Antimicrob Agents Chemother 50: 1365-1371.
Hiller, D., Stahl, S., and Morschhäuser, J. (2006) Multiple cis-acting sequences mediate upregulation of the MDR1 efflux pump
in a fluconazole-resistant, clinical Candida albicans isolate. Antimicrob Agents Chemother 50: 2300-2308.
Hochhut, B., Dobrindt, U., Hacker, J. (2005) Pathogenicity islands and their role in bacterial virulence and survival. Contrib.
Microbiol., 12, 234 – 254.
Hochhut, B., Dobrindt, U., Hacker, J. (2006) Pathogenicity islands. In: Evolution of microbial pathogens (H. Seifert, V. di Rita,
eds.) ASM Press, Washington D.C. 83-107.
Hochhut, B., Wilde, C., Balling, G., Middendorf, B., Dobrindt, U., Brzuszkiewicz, E., Gottschalk, G., Carniel, E., Hacker, J. (2006)
Role of pathogenicity island-associated integrases in the genome plasticity of uropathogenic Escherichia coli strain 536.
Mol. Microbiol. 61: 584-595.
Holden, N. J., Totsika, M., Mahler, E., Roe, A. J., Catherwood, K., Lindner, K., Dobrindt, U., Gally, D. L. (2006) Demonstration of
regulatory cross-talk between P-fimbriae and type 1 fimbriae in uropathogenic Escherichia coli. Microbiology 152: 11431153.
Horstmann, M., Ehses, P., Schweimer, K., Steinert, M., Kamphausen, T., Fischer, G.,Hacker, J., Rosch, P., Faber, C. (2006)
Domain Motions of the Mip Protein from Legionella pneumophila. Biochemistry. 45, 12303-12311.
Horstmann, M., Kamphausen, T., Schweimer, K., Steinert, M., Hacker, J., Haase, A., Rösch, P., Fischer, G., Faber, C. (2005) 1H,
13C, 15N backbone and sidechain resonance assignment of Mip(77-213) the PPIase domain of the Legionella
pneumophila Mip protein. J. Biomol. NMR. 31: 77-78.
Janka, A., Becker, G., Sonntag, A.-K., Bielaszewska, M., Dobrindt, U., Karch, H., (2005) Presence and Characterization of a
Mosaic Genomic Island Which Distinguishes Sorbitol-Fermenting Enterohemorrhagic Escherichia coli O157:H- from E.
coli O157:H7. Appl. Environ. Microbiol. 71: 4875-4878.
K. Ohlsen and J. Hacker. Infections in the elderly. (2006) Int. J. Med. Microbiol. 294:471-472.
Körner, U., V. Fuss, J. Steigerwald and H. Moll (2006). The biogenesis of Leishmania major-harboring vacuoles in dendritic
cells. Infect. Immun. 74: 1305-1312.
Kouokam, J. C., Nyunt Wai, S., Dobrindt, U., Hacker, J., Uhlin, B. E. (2006) Active cytotoxic necrotizing factor 1 associated with
outer membrane vesicles from uropathogenic E. coli. Infect. Immun. 74: 2022-2030.
Kozitskaya S, Olson ME, Fey PD, Witte W, Ohlsen K, Ziebuhr W. (2005) Clonal analysis of Staphylococcus epidermidis isolates
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carrying or lacking biofilm-mediating genes by multilocus sequence typing. J Clin Microbiol. 43 4751-7.
Michel, A., Agerer, F., Hauck, C.F., Herrmann, M., Ullrich, J., Hacker, J., Ohlsen, K. (2006) Global regulatory impact of ClpP
protease of Staphylococcus aureus on regulons involved in virulence, oxidative stress response, autolysis, and DNA
repair. J. Bacteriol., 188, 5783-5796.
Moll, H. (2006). Dendritic cells in leishmaniasis: Regulators of immunity and tool for new immune intervention strategies. In:
Handbook of Dendritic Cells – Biology, Diseases and Therapies, M. B. Lutz, A. Steinkasserer and N. Romani (eds.), WileyVCH, Weinheim, Germany, pp. 669-691.
Morschhäuser, J., Staib, P., and Köhler, G. (2005) CARE-2 fingerprinting of Candida albicans isolates. Methods Mol Med 118:
27-34.
Morschhäuser, J., Staib, P., and Köhler, G. (2005) Targeted gene deletion in Candida albicans wild-type strains by MPARflipping. Methods Mol Med 118: 35-44.
Müller, C. M., Dobrindt, U., Nagy, G., Emödy, L., Uhlin, B.E., Hacker, J. (2006) Role of Histone-like Proteins H-NS and StpA in
Expression of Virulence Determinants of uropathogenic Escherichia coli. J. Bacteriol. 188: 5428-5438.
Nougayrède, J.-P., Homburg, S., Taieb, F., Boury, M., Brzuszkiewicz, E., Gottschalk, G., Buchrieser, C., Hacker, J., Dobrindt, and
U., Oswald, E. (2006) Escherichia coli induces DNA double strand breaks in eukaryotic cells. Science 313:848-851.
Nagy, G., Dobrindt, U., Grozdanov, L., Hacker, J., and Emody, L. (2005) Transcriptional regulation through RfaH contributes to
intestinal colonization by Escherichia coli. FEMS Microbiol Lett 244: 173-180.
Nagy, G., Altenhoefer, A., Knapp, O., Maier, E., Dobrindt, U., Blum-Oehler, G., Benz, R., Emody, L., and Hacker, J. (2006) Both
alpha-haemolysin determinants contribute to full virulence of uropathogenic Escherichia coli strain 536. Microbes Infect
8: 2006-2012.
Nagy, G., Danino, V., Dobrindt, U., Pallen, M., Chaudhuri, R., Emody, L., Hinton, J.C., and Hacker, J. (2006) Down-regulation of
key virulence factors makes the Salmonella enterica serovar Typhimurium rfaH mutant a promising live-attenuated
vaccine candidate. Infect Immun 74: 5914-5925.
Streker K., Freiberg, C., Labischinski, H., Hacker, J, Ohlsen K. (2005) Staphylococcus aureus NfrA (SA0367) is a flavin
mononucleotide-dependent NADPH oxidase involved in oxidative stress response. J Bacteriol. 187, 2249-2256.
Taylor, B., Staib, P., Binder, A., Biesemeier, A., Sehnal, M., Röllinghoff, M., Morschhäuser, J., and Schröppel, K. (2005) Profile
of Candida albicans-secreted aspartic proteinase elicited during vaginal infection. Infect Immun 73: 1828-1835.
Theiss, S., Ishdorj, G., Brenot, A., Kretschmar, M., Lan, C.Y., Nichterlein, T., Hacker, J., Nigam. S., Agabian, N., Kohler, G.A.
(2006) Inactivation of the phospholipase B gene PLB5 in wild-type Candida albicans reduces cell-associated
phospholipase A(2) activity and attenuates virulence. Int J Med Microbiol. 296, 405-420.
Trujillo-Vargas, C. M., J. R. Ramírez-Pineda, A. Palmetshofer, S. Grunewald, H. Moll, C. Berberich and K. J. Erb (2005). Mice
vaccinated with allergen-pulsed myeloid dendritic cells are not protected from developing allergen-induced Th2 responses.
Int. Arch. Allergy Immunol. 137: 219-228.
Vicik, R., V. Hoerr, M. Glaser, M. Schultheis, E. Hansell, J. H. McKerrow, U. Holzgrabe, C. R. Caffrey, A. Ponte-Sucre, H. Moll, A.
Stich and T. Schirmeister (2006). Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg. Med. Chem. Letters 16: 2753-2757.
Ziebuhr W, Hennig S, Eckart M, Kranzler H, Batzilla C, Kozitskaya S. (2006) Nosocomial infections by Staphylococcus epidermidis:
how a commensal bacterium turns into a pathogen. Int J Antimicrob Agents. 2006 Aug;28 Suppl 1:S14-20. Epub Jul 7.
3-6 Institute of Pathology :
Adam, P., Katzenberger, T., Eifert, M., Ott, M.M., Rosenwald, A., Muller-Hermelink, H.K., and Ott, G. (2005) Presence of preserved
reactive germinal centers in follicular lymphoma is a strong histopathologic indicator of limited disease stage. Am J Surg
Pathol 29: 1661-1664.
Adam, P., Zettl, A., Zollner, U., Dietl, J., Muller-Hermelink, H.K., and Eck, M. (2005) Metastasizing vulvar carcinosarcoma with
squamous carcinomatous and leiomyosarcomatous differentiation: genetic evidence of clonal origin. Hum Pathol 36:
1143-1147.
Adam, P., Steinlein, C., Schmid, M., Haralambieva, E., Stocklein, H., Leich, E., Rosenwald, A., Muller-Hermelink, H.K., and Ott,
G. (2006) Characterization of chromosomal aberrations in diffuse large B-cell lymphoma (DLBL) by G-banding and
spectral karyotyping (SKY). Cytogenet Genome Res 114: 274-278.
Ballova, V., Ruffer, J.U., Haverkamp, H., Pfistner, B., Muller-Hermelink, H.K., Duhmke, E., Worst, P., Wilhelmy, M., Naumann, R.,
Hentrich, M., Eich, H.T., Josting, A., Loffler, M., Diehl, V., and Engert, A. (2005) A prospectively randomized trial carried out
by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP
baseline and COPP-ABVD (study HD9elderly). Ann Oncol 16: 124-131.
Bea, S., Zettl, A., Wright, G., Salaverria, I., Jehn, P., Moreno, V., Burek, C., Ott, G., Puig, X., Yang, L., Lopez-Guillermo, A., Chan,
W.C., Greiner, T.C., Weisenburger, D.D., Armitage, J.O., Gascoyne, R.D., Connors, J.M., Grogan, T.M., Braziel, R., Fisher,
R.I., Smeland, E.B., Kvaloy, S., Holte, H., Delabie, J., Simon, R., Powell, J., Wilson, W.H., Jaffe, E.S., Montserrat, E., Muller-
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107
Hermelink, H.K., Staudt, L.M., Campo, E., and Rosenwald, A. (2005) Diffuse large B-cell lymphoma subgroups have
distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106:
3183-3190.
Brighenti, A., Andrulis, M., Geissinger, E., Roth, S., Muller-Hermelink, H.K., and Rudiger, T. (2005) Extrafollicular proliferation of
B cells in the absence of follicular hyperplasia: a distinct reaction pattern in lymph nodes correlated with primary or recall
type responses. Histopathology 47: 90-100.
Cejkova, P., Zettl, A., Baumgartner, A.K., Chott, A., Ott, G., Muller-Hermelink, H.K., and Starostik, P. (2005) Amplification of
NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma. Virchows Arch 446: 416-420.
Chanudet, E., Zhou, Y., Bacon, C.M., Wotherspoon, A.C., Muller-Hermelink, H.K., Adam, P., Dong, H.Y., de Jong, D., Li, Y., Wei,
R., Gong, X., Wu, Q., Ranaldi, R., Goteri, G., Pileri, S.A., Ye, H., Hamoudi, R.A., Liu, H., Radford, J., and Du, M.Q. (2006)
Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions. J Pathol
209: 344-351.
Chuang, W.Y., Strobel, P., Gold, R., Nix, W., Schalke, B., Kiefer, R., Opitz, A., Klinker, E., Muller-Hermelink, H.K., and Marx, A.
(2005) A CTLA4high genotype is associated with myasthenia gravis in thymoma patients. Ann Neurol 58: 644-648.
Dave, S.S., Fu, K., Wright, G.W., Lam, L.T., Kluin, P., Boerma, E.J., Greiner, T.C., Weisenburger, D.D., Rosenwald, A., Ott, G.,
Muller-Hermelink, H.K., Gascoyne, R.D., Delabie, J., Rimsza, L.M., Braziel, R.M., Grogan, T.M., Campo, E., Jaffe, E.S.,
Dave, B.J., Sanger, W., Bast, M., Vose, J.M., Armitage, J.O., Connors, J.M., Smeland, E.B., Kvaloy, S., Holte, H., Fisher, R.I.,
Miller, T.P., Montserrat, E., Wilson, W.H., Bahl, M., Zhao, H., Yang, L., Powell, J., Simon, R., Chan, W.C., and Staudt, L.M.
(2006) Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med 354: 2431-2442.
Engert, A., Ballova, V., Haverkamp, H., Pfistner, B., Josting, A., Duhmke, E., Muller-Hermelink, K., and Diehl, V. (2005) Hodgkin’s
lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin’s Study Group. J Clin
Oncol 23: 5052-5060.
Fu, K., Weisenburger, D.D., Greiner, T.C., Dave, S., Wright, G., Rosenwald, A., Chiorazzi, M., Iqbal, J., Gesk, S., Siebert, R., De
Jong, D., Jaffe, E.S., Wilson, W.H., Delabie, J., Ott, G., Dave, B.J., Sanger, W.G., Smith, L.M., Rimsza, L., Braziel, R.M.,
Muller-Hermelink, H.K., Campo, E., Gascoyne, R.D., Staudt, L.M., and Chan, W.C. (2005) Cyclin D1-negative mantle cell
lymphoma: a clinicopathologic study based on gene expression profiling. Blood 106: 4315-4321.
Gattenlohner, S., Bonengel, M., and Muller-Hermelink, H.K. (2006) [Optimized RT-PCR based detection of specific genetic
abnormalities within malignant hematopoietic disorders]. Pathologe 27: 182-187.
Gattenlohner, S., Marx, A., Markfort, B., Pscherer, S., Landmeier, S., Juergens, H., Muller-Hermelink, H.K., Matthews, I., Beeson,
D., Vincent, A., and Rossig, C. (2006) Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based
chimeric receptor targeting the fetal acetylcholine receptor. Cancer Res 66: 24-28.
Geissinger, E., Bonzheim, I., Krenacs, L., Roth, S., Strobel, P., Ott, G., Reimer, P., Wilhelm, M., Muller-Hermelink, H.K., and
Rudiger, T. (2005) Identification of the tumor cells in peripheral T-cell lymphomas by combined polymerase chain reactionbased T-cell receptor beta spectrotyping and immunohistological detection with T-cell receptor beta chain variable region
segment-specific antibodies. J Mol Diagn 7: 455-464.
Geissinger, E., Adam, P., Muller-Hermelink, H.K., and Rudiger, T. (2006) [Cutaneous B-cell lymphoma: Classification and
diagnostics.]. Pathologe.
Geissinger, E., Bonzheim, I., Krenacs, L., Roth, S., Reimer, P., Wilhelm, M., Muller-Hermelink, H.K., and Rudiger, T. (2006)
Nodal peripheral T-cell lymphomas correspond to distinct mature T-cell populations. J Pathol 210: 172-180.
Girschick, H.J., Raab, P., Surbaum, S., Trusen, A., Kirschner, S., Schneider, P., Papadopoulos, T., Muller-Hermelink, H.K., and
Lipsky, P.E. (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64: 279-285.
Greiner, T.C., Dasgupta, C., Ho, V.V., Weisenburger, D.D., Smith, L.M., Lynch, J.C., Vose, J.M., Fu, K., Armitage, J.O., Braziel,
R.M., Campo, E., Delabie, J., Gascoyne, R.D., Jaffe, E.S., Muller-Hermelink, H.K., Ott, G., Rosenwald, A., Staudt, L.M., Im,
M.Y., Karaman, M.W., Pike, B.L., Chan, W.C., and Hacia, J.G. (2006) Mutation and genomic deletion status of ataxia
telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc Natl Acad
Sci U S A 103: 2352-2357.
Haralambieva, E., Boerma, E.J., van Imhoff, G.W., Rosati, S., Schuuring, E., Muller-Hermelink, H.K., Kluin, P.M., and Ott, G.
(2005) Clinical, immunophenotypic, and genetic analysis of adult lymphomas with morphologic features of Burkitt
lymphoma. Am J Surg Pathol 29: 1086-1094.
Haralambieva, E., Adam, P., Ventura, R., Katzenberger, T., Kalla, J., Holler, S., Hartmann, M., Rosenwald, A., Greiner, A., MullerHermelink, H.K., Banham, A.H., and Ott, G. (2006) Genetic rearrangement of FOXP1 is predominantly detected in a subset
of diffuse large B-cell lymphomas with extranodal presentation. Leukemia 20: 1300-1303.
Hummel, M., Bentink, S., Berger, H., Klapper, W., Wessendorf, S., Barth, T.F., Bernd, H.W., Cogliatti, S.B., Dierlamm, J., Feller,
A.C., Hansmann, M.L., Haralambieva, E., Harder, L., Hasenclever, D., Kuhn, M., Lenze, D., Lichter, P., Martin-Subero, J.I.,
Moller, P., Muller-Hermelink, H.K., Ott, G., Parwaresch, R.M., Pott, C., Rosenwald, A., Rosolowski, M., Schwaenen, C.,
Sturzenhofecker, B., Szczepanowski, M., Trautmann, H., Wacker, H.H., Spang, R., Loeffler, M., Trumper, L., Stein, H., and
Siebert, R. (2006) A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med 354:
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2419-2430.
Iqbal, J., Neppalli, V.T., Wright, G., Dave, B.J., Horsman, D.E., Rosenwald, A., Lynch, J., Hans, C.P., Weisenburger, D.D.,
Greiner, T.C., Gascoyne, R.D., Campo, E., Ott, G., Muller-Hermelink, H.K., Delabie, J., Jaffe, E.S., Grogan, T.M., Connors,
J.M., Vose, J.M., Armitage, J.O., Staudt, L.M., and Chan, W.C. (2006) BCL2 expression is a prognostic marker for the
activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol 24: 961-968.
Katzenberger, T., Petzoldt, C., Holler, S., Mader, U., Kalla, J., Adam, P., Ott, M.M., Muller-Hermelink, H.K., Rosenwald, A., and Ott,
G. (2006) The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood 107: 3407.
Muller-Hermelink, H.K. (2006). Pathologe.
Nogova, L., Reineke, T., Eich, H.T., Josting, A., Muller-Hermelink, H.K., Wingbermuhle, K., Brillant, C., Gossmann, A., Oertel, J.,
Bollen, M.V., Muller, R.P., Diehl, V., and Engert, A. (2005) Extended field radiotherapy, combined modality treatment or
involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective
analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 16: 1683-1687.
Nogova, L., Reineke, T., Josting, A., Muller-Hermelink, H.K., Eich, H.T., Behringer, K., Muller, R.P., Diehl, V., and Engert, A. (2005)
Lymphocyte-predominant and classical Hodgkin’s lymphoma—comparison of outcomes. Eur J Haematol Suppl: 106110.
Rimsza, L.M., Roberts, R.A., Campo, E., Grogan, T.M., Bea, S., Salaverria, I., Zettl, A., Rosenwald, A., Ott, G., Muller-Hermelink,
H.K., Delabie, J., Fisher, R.I., Unger, J.M., Leblanc, M., Staudt, L.M., Jaffe, E.S., Gascoyne, R.D., Chan, W.C., Weisenburger,
D.D., Greiner, T., Braziel, R.M., and Miller, T.P. (2006) Loss of major histocompatibility class II expression in non-immuneprivileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions. Blood 107:
1101-1107.
Roberts, R.A., Wright, G., Rosenwald, A.R., Jaramillo, M.A., Grogan, T.M., Miller, T.P., Frutiger, Y., Chan, W.C., Gascoyne, R.D.,
Ott, G., Muller-Hermelink, H.K., Staudt, L.M., and Rimsza, L.M. (2006) Loss of major histocompatibility class II gene and
protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient
survival. Blood 108: 311-318.
Rudiger, T., Geissinger, E., and Muller-Hermelink, H.K. (2006) ‘Normal counterparts’ of nodal peripheral T-cell lymphoma.
Hematol Oncol 24: 175-180.
Rudiger, T., Zettl, A., Adam, P., Bonzheim, I., Geissinger, E., and Muller-Hermelink, H.K. (2006) [Peripheral NK/T-cell lymphoma.].
Pathologe.
Schmausser, B., Andrulis, M., Endrich, S., Muller-Hermelink, H.K., and Eck, M. (2005) Toll-like receptors TLR4, TLR5 and TLR9
on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol 295: 179-185.
Schmausser, B., Endrich, S., Brandlein, S., Schar, J., Beier, D., Muller-Hermelink, H.K., and Eck, M. (2005) The chemokine
receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma
and its precursor lesions and up-regulated by H. pylori. Clin Exp Immunol 139: 323-327.
Sonnen, R., Schmidt, W.P., Muller-Hermelink, H.K., and Schmitz, N. (2005) The International Prognostic Index determines the
outcome of patients with nodal mature T-cell lymphomas. Br J Haematol 129: 366-372.
Strobel, P., Marino, M., Feuchtenberger, M., Rouziere, A.S., Tony, H.P., Wulbrand, U., Forster, R., Zettl, A., Lee Harris, N., Kreipe,
H., Laeng, R.H., Muller-Hermelink, H.K., and Marx, A. (2005) Micronodular thymoma: an epithelial tumour with abnormal
chemokine expression setting the stage for lymphoma development. J Pathol 207: 72-82.
Strobel, P., Marx, A., Zettl, A., and Muller-Hermelink, H.K. (2005) Thymoma and thymic carcinoma: an update of the WHO
Classification 2004. Surg Today 35: 805-811.
van den Brandt, J., Kwon, S.H., McPherson, K.G., Petrovic, S., Zettl, A., Muller-Hermelink, H.K., and Reichardt, H.M. (2006)
Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats. Eur J Immunol 36: 2223-2234.
Zettl, A., Rudiger, T., Marx, A., Muller-Hermelink, H.K., and Ott, G. (2005) Composite marginal zone B-cell lymphoma and
classical Hodgkin’s lymphoma: a clinicopathological study of 12 cases. Histopathology 46: 217-228.
3-7 Medical Clinic I,
(in the field of Immunology and Infectiology):
Nahrendorf M, Hu K, Frantz S, Jaffer FA, Tung CH, Hiller KH, Voll S, Nordbeck P, Sosnovik D, Gattenlohner S, Novikov M,
Dickneite G, Reed GL, Jakob P, Rosenzweig A, Bauer WR, Weissleder R, Ertl G (2006) Factor XIII deficiency causes
cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation.
113(9):1196-202.
Kuhlencordt P, Hötten S, Schödel J, Rützel S, Hu K, Widder J, Marx A, Huang PL, Ertl G (2006) Atheroprotective effects of
neuronal nitric oxide synthase in apolipoprotein e knockout mice.Arterioscler Thromb Vasc Biol.26(7):1539-44.
Bauersachs J, Thum T, Frantz S, Ertl G (2005) Cardiac regeneration by progenitor cells—bedside before bench? Eur J Clin
Invest. 35(7):417-20
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3-8 Medical Clinic II, Clinical Infectiology (in the field of Immunology and Infectiology):
A. Benesic, M. Zilly, H. Klinker, P. Langmann (2005). HIV-protease4 inhibitors show no effects on viability and intracellular
Ca2+ in human proximal tubular cells in primary culture. Eur J Med Res 10: 82
A. Bergk, P. Buggisch, C. Sarrazin, G. Teuber, H. Klinker, B. Wiedemann, T. Berg (2005). Der Nachweis einer minimalen
Hepatitis C Virämie 12 Wochen nach Therapiebeginn ist mit einer hohen Relapserate assoziiert. Z Gastroenterol 43:
852
A. Helle, W. Heinz, V. Kunzmann, H. Klinker, H. Einsele (2006). Recurrent malignat schwannoma with an intracardial tumor
manifestation: a case report. Onkologie 29 (Suppl 3): 149
A. Knipper, P. Langmann, M. Zilly, R. Winzer, H. Klinker (2005). Visceral leishmaniasis as a reason for tricytopenia under
retroviral treatment of HIV-infection. Eur J Med Res 10: 105-106
A. Trein, P. Langmann, M. Zilly, H. Klinker, E. Schnaitmann (2005). Efficacy and safety of a combination of lopinavir and
efavirenz or nevirapine in a nuke free regimen. Eur J Med Res 10: 80
B. Schöttker, W. Heinz, F. Weissinger, K. Sözener, M. Eck, J. Seufert (2006). Parathyroid Hormone-Related Protein-Associated
Hypercalcemia in a Patient with CLL Type Low Grade Leukemic B-Cell Lymphoma. Haematologica/the hematology
journal; 91 (online)
Beck O, Topp MS, Koehl U, Roilides E, Simitsopoulou M, Hanisch M, Sarfati J, Latge JP, Klingebiel T, Einsele H, Lehrnbecher
T. Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus. Blood. 2006 Mar
15;107(6):2562-9..
Bethge WA, Schmalzing M, Stuhler G, Schumacher U, Krober SM, Horger M, Einsele H, Kanz L, Hebart H. Mucormycoses in
patients with hematologic malignancies: an emerging fungal infection. Haematologica. 2005
Bissinger AL, Brugger J, Grigoleit GU, Grundemann C, Hebart H, Einsele H, Jahn G. Visualization and microscopic
quantification of HCMV-peptide-specific cytotoxic T lymphocytes using tetramer binding. Viral Immunol. 2005;18(3):5348
Bissinger AL, Einsele H, Hamprecht K, Schumacher U, Kandolf R, Loeffler J, Aepinus C, Bock T, Jahn G, Hebart H. Infectious
pulmonary complications after stem cell transplantation or chemotherapy: diagnostic yield of bronchoalveolar lavage.
Diagn Microbiol Infect Dis. 2005 Aug;52(4):275-80
Brodoefel H, Vogel M, Hebart H, Einsele H, Vonthein R, Claussen C, Horger M. Long-term CT follow-up in 40 non-HIV
immunocompromised patients with invasive pulmonary aspergillosis: kinetics of CT morphology and correlation with
clinical findings and outcome. AJR Am J Roentgenol. 2006 Aug;187(2):404-13.
Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, Juliusson G, Ahlberg L, Nagler A, Shimoni A, Sureda
A, Boiron JM, Einsele H, Chopra R, Carella A, Cavenagh J, Gratwohl A, Garban F, Zander A, Bjorkstrand B, Niederwieser
D, Gahrton G, Apperley JF. Outcomes for reduced intensity allogeneic transplantation for multiple myeloma: an analysis
of prognostic factors from the chronic leukemia working party of the EBMT. Blood. 2005 Jun 1;105(11):4532-9.
D. Tappe, R. Winzer, P. Ströbel, A. Stich, H. Klinker, M. Frosch (2006). Linguatuliasis in Germany. Emerging Infectious
Diseases 12: 1034-1036
Daikeler T, Erley C, Mohren M, Amberger C, Einsele H, Kanz L, Kotter I.Fever and increasing cANCA titre after kidney and
autologous stem cell transplantation for Wegener’s granulomatosis. Ann Rheum Dis. 2005 Apr;64(4):646-7
E. Schott, H. Witt, G. Teuber, C. Sarrazin, H. Klinker, P. Buggisch, B. Wiedenmann, T. Berg (2005). Assoziation von Single
Nukleotide Polymorphismen (SNPs) des cytotoxic T lmphocyte antigene-4 (CTLA-4) Gens mit dem Ansprechen auf
eine PegInterferon-alpha2b/Ribavirin Kombinationstherapie bei Patienten mit chronischer Hepatitis C (HCV-)-Infektion.
Z Gastroenterol 43: 840
Einsele H. T-cell therapy for viral and fungal infections. Blood 2005, 106(13)
Einsele H., Pierre Reusser, Martin Bornhäuser, Peter Kalhs, Gerhard Ehninger, Holger Hebart, Yves Chalandon, Nicolaus
Kröger, Bernd Hertenstein, Frank Rohde.Oral valganciclovir leads to higher exposure to ganciclovir than intravenous
ganciclovir in patients following allogeneic stem cell transplantation.Blood. 2006 Apr 1;107(7):3002-8
Graham J, Einsele H, Moreau P, San Miguel J. Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic
malignancies. Cancer Treatment Reviews, Volume 31, Issue 8, December 2005, Pages 591-602
Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P, Einsele H, Cordonnier C; Acute and Chronic
Leukemia Working Parties; Infectious Diseases Working Party of the European Group for Blood and Marrow
Transplantation. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias:
an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005
Nov;36(9):757-69
H. Klinker (2005). Pharmakologische Interaktionen bei der antiretroviralen Therapie. Arzneimitteltherapie 23: 80-88
H. Klinker (2005). Therapie der chronischen Hepatitis C: Was ist bei „Problempatienten“ zu beachten? Klinikarzt 34: 140145
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H. Klinker (2006). Ribavirinspiegelmessung – Pro und Contra aus klinischer Sicht. In: J. Rockstroh, S. Mauss, H. Jäger
(Hrsg.): Koinfektion Hepatitis und HIV, Band 4, Georg Thieme Verlag Stuttgart New York, S. 85-88
H. Klinker, P. Langmann, R. Winzer (2006). Oft kombiniert, wenig untersucht - Proteasehemmer und Interaktionen. In: C.
Hoffmann, H. Jäger (Hrsg.): AIDS-Monographien, Band 11, „AIDS 2006: Wunschwelt Heilung – Evidenz für Fortschritt
oder Stillstand?“, 178-182
Horger M, Einsele H, Schumacher U, Wehrmann M, Hebart H, Lengerke C, Vonthein R, Claussen CD, Pfannenberg C.
Invasive pulmonary aspergillosis: frequency and meaning of the „hypodense sign“ on unenhanced CT. Br J Radiol.
2005 Aug;78(932):697-703
Horger M, Hebart H, Einsele H, Lengerke C, Claussen CD, Vonthein R, Pfannenberg C. Initial CT manifestations of invasive
pulmonary aspergillosis in 45 non-HIV immunocompromised patients: association with patient outcome? Eur J Radiol.
2005 Sep;55(3):437-44
Horger M, Lengerke C, Pfannenberg C, Wehrmann M, Einsele H, Knop S, Claussen CD. Significance of the „halo“ sign for
progression and regression of nodular pulmonary amyloidosis: radiographic-pathological correlation (2005:6b).Eur
Radiol. 2005 Sep;15(9):2037-40
J. Halangk, H. Witt, C. Sarrazin, G. Puhl, G. Teuber, H. Klinker, P. Buggisch, H. Hinrichsen, V. Weich, A. Bergk, B. Wiedenmann,
P. Neuheus, W. Luck, T. Berg (2006). Bedeutung von Polymorphismen des Komplementfaktor 5 auf die
Fibroseprogression bei chronischen Lebererkrankungen. Z Gastroenterol 44: 83
Karthaus M, Hebart H, Einsele H, Schaefer H, Scheel-Walter H, Buchheidt D, Lehrnbecher T. Long-term survival in patients
with acute leukemia and chronic disseminated candidiasis despite minimal antileukemic therapy. Haematologica.
2006 Oct;91(10):1422-3.
Kruger WH, Bohlius J, Cornely OA, Einsele H, Hebart H, Massenkeil G, Schuttrumpf S, Silling G, Ullmann AJ, Waldschmidt
DT, Wolf HH. Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases
working party (AGIHO) of the german society of haematology and oncology. Ann Oncol. 2005 Aug;16(8):1381-90
Lengerke C, Ljubicic T, Meisner C, Loeffler J, Sinzger C, Einsele H, Hebart H. Evaluation of the COBAS Amplicor HCMV
Monitor for early detection and monitoring of human cytomegalovirus infection after allogeneic stem cell transplantation.
Bone Marrow Transplant. 2006 Jul;38(1):53-60
Liebisch P, Scheck D, Erne SA, Wellmann A, Wendl C, Janczik S, Kolmus S, Krober A, Einsele H, Straka C, Goldschmidt H,
Benner A, Stilgenbauer S, Dohner H. Duplication of chromosome arms 9q and 11q: evidence for a novel, 14q32
translocation-independent pathogenetic pathway in multiple myeloma.Genes Chromosomes Cancer. 2005 Jan;42(1):7881
Ljungman P, Engelhard D, de la Camara R, Einsele H, Locasciulli A, Martino R, Ribaud P, Ward K, Cordonnier C; Infectious
Diseases Working Party of the European Group for Blood and Marrow Transplantation.Vaccination of stem cell transplant
recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant. 2005
Apr;35(8):737-46.
Loeffler J, Steffens M, Arlt EM, Toliat MR, Mezger M, Suk A, Wienker TF, Hebart H, Nurnberg P, Boeckh M, Ljungman P,
Trenschel R, Einsele H. Polymorphisms in the genes encoding chemokine receptor 5, interleukin-10, and monocyte
chemoattractant protein 1 contribute to cytomegalovirus reactivation and disease after allogeneic stem cell
transplantation. J Clin Microbiol. 2006 May;44(5):1847-50.
M. Hartmann, J. Brust, D. Schuster, F. Mosthaf, M. Procaccianti, J. A. Rump, H. Klinker, D. Petzold (2005). Arzneimittelexantheme
bei Therapie der HIV-Infektion mit Efavirenz und Nevirapin. Hautarzt 56: 847-853
M. Hartmann, S. Witte, J. Brust, D. Schuster, F. Mosthaf, M. Procaccianti, A. Rump, H. Klinker, D. Petzoldt (2005). Comparison
of Efavirenz and Nevirapine in HIV-infected patients (NEEF Cohort). Int J STD & AIDS 16: 404-409
Mandle T, Einsele H, Schaller M, Neumann D, Vogel W, Autenrieth IB, Kempf VA. Infection of human CD34+ progenitor cells
with Bartonella henselae results in intraerythrocytic presence of B. henselae. Blood. 2005 Aug 15;106(4):1215-22.
Mandle T, Einsele H, Schaller M, Neumann D, Vogel W, Autenrieth IB, Kempf VA. Infection of human CD34+ progenitor cells
with Bartonella henselae results in intraerythrocytic presence of B. henselae. Blood. 2005 Aug 15;106(4):1215-22
Martino R, Bretagne S, Einsele H, Maertens J, Ullmann AJ, Parody R, Schumacher U, Pautas C, Theunissen K, Schindel C,
Munoz C, Margall N, Cordonnier C; Infectious Disease Working Party of the European Group for Blood and Marrow
Transplantation. Early detection of Toxoplasma infection by molecular monitoring of Toxoplasma gondii in peripheral
blood samples after allogeneic stem cell transplantation. Clin Infect Dis. 2005 Jan 1;40(1):67-78.
Martino R, Parody R, Fukuda T, Maertens J, Theunissen K, Ho A, Mufti GJ, Kroger N, Zander AR, Heim D, Paluszewska M,
Selleslag D, Steinerova K, Ljungman P, Cesaro S, Nihtinen A, Cordonnier C, Vazquez L, Lopez-Duarte M, Lopez J,
Cabrera R, Rovira M, Neuburger S, Cornely O, Hunter AE, Marr KA, Dornbusch HJ, Einsele H. Impact of the intensity of
the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic
hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European
Group for Blood and Marrow Transplantation. Blood. 2006 Nov 1;108(9):2928-36.
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111
N. Venhoff, M. Zilly, D. Lebrecht, D. Schirmer, H. Klinker, J. Thoden, P. Langmann, U. Walker (2005). Uridine pharmacokinetics
of mitocnol, a sugar cane Extract. AIDS 19: 739-740
P Ljungman, A Urbano-Ispizua, M Cavazzana-Calvo, T Demirer, G Dini, H Einsele, A Gratwohl, A Madrigal, D Niederwieser,
J Passweg, V Rocha, R Saccardi, H Schouten, N Schmitz, G Socie,A Sureda, and J Apperley for the European Group for
Blood and Marrow Transplantation. Allogeneic and autologous transplantation for haematological diseases,
solidtumours and immune disorders: definitions and current practice in Europe. Bone Marrow Transplant. 2006
Mar;37(5):439-49.
P. Langmann, A. Trein, M. Zilly, H. Klinker, E. Schnaitmann (2005). Safety of lopinavir through plasmalevels in combination
with NNRTI in a nuke free regimen. Eur J Med Res 10: 78-79
P. Langmann, D. Schirmer, H. Klinker (2006). Therapeutisches Dtrug Monitoring von Ribavirin – ein Parameter zur
Individualisierung der HCV-Therapie. Med Klin 101: 104
P. Langmann, H. Klinker (2005). Koinfektion HIV und Hepatitis C. In: H. Jäger(Hrsg.): AIDS und HIV-Infektionen. Handbuch
und Atlas für Klinik und Praxis. Ecomed Verlagsgesellschaft 1987ff (2005), V- 3.1.2, S. 1-14
P. Langmann, H. Klinker (2006). Pharmakologie und Therapeutisches Drug Monitoring.In: J. R. Bogner (Hrsg):
Proteasehemmer in der HIV-Therapie, UNI-MED-Verlag Bremen London Boston, S. 89-98
P. Langmann, L. Schneider, M. Zilly, R. Winzer, H. Klinker (2005). Boosted double PI therapy in a patient with liver cirrhosis
and NRTI-induced lactic acidosis. Eur J Med Res 10: 103
P. Langmann, M. Zilly, A. Katsounas, R. Winzer, A. Emmert, A. Knipper, H. Klinker (2005). Efavirenz long term therapy: no
change of EFV levels. Eur J Med Res 10: 79
P. Langmann, M. Zilly, C. Hubert, R. Winzer, A. Emmert, H. Klinker (2005). Liver enzyme elevation in a LPV/r based therapy
i soften only slight and mainly caused by GGT. Eur J Med Res 10: 79
P. Langmann, M. Zilly, R. Winzer, H. Klinker (2006). Therapeutic Drug Monitoring: A Tool to Individualize Highly Active Antiretroviral
Therapy in HIV Infected Patients. Current Pharmaceutical Analysis 2: 205-217
Penack O, Beinert T, Buchheidt D, Einsele H, Hebart H, Kiehl MG, Massenkeil G, Schiel X, Schleicher J, Staber PB, Wilhelm
S, Wolf HH, Ostermann H; German Society of Hematology and Oncology. Management of sepsis in neutropenia:
guidelines of the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology
(DGHO).Ann Hematol. 2006 Jul;85(7):424-33
R. Eckert, M. Zilly, D. Schirmer, R. Winzer, H. Klinker, P. Langmann (2005). Uridine plasma levels of HIV-1 positive patients
under antiretroviral therapy. Eur J Med Res 10: 111
R. Seggewiß, W. Heinz, V. Kunzmann, H. Klinker, H. Einsele (2006). Progressive multifocal leukencephalopathy after
allogenic stem cell transplantation in multiple myeloma. Onkologie 29 (Suppl 3): 185-186
R. Winzer, P. Langmann, M. Zilly, D. Schirmer, B. Weissbrich, H. Klinker (2005). Interpretation of untimed lopinavir (LPV) drug
levels – use in clinical practice. Eur J Med Res 10: 116
R. Winzer, P. Langmann, M. Zilly, F. Tollmann, J. Schubert, H. Klinker, B. Weissbrich (2005). No influence of the P-glycoprotein
polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naive HIVpositive patients. Annals of Clinical Microbiology and Antimicrobials (online) 4(1):3
R. Winzer, P. Langmann, M. Zilly, F. Tollmann, J. Schubert, H. Klinker, B. Weißbrich (2005). Kein Einfluss des P-GlykoproteinGenotyps (MDR1 C3435T) auf die virologische und immunologische Response therapienaiver HIV-Patienten. Med.
Klinik 100: 91
R. Winzer, P. Langmann, M. Zilly, F. Tollmann, J. Schubert, H. Klinker, B. Weissbrich (2005). No influence of the P-glycoprotein
polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naïve HIVpositive patients. Eur J Med Res 10: 78
Reich G, Cornely OA, Sandherr M, Kubin T, Krause S, Einsele H, Thiel E, Bellaire T, Dörken and Maschmeyer G. Empirical
antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a
randomised, multicentre trial. Br J of Haematol 2005 (130):265-270
S.E. Eckert, W. J. Heinz, K. Zakikhany, S. Thewes, K. Haynes, B. Hube, F. A. Mühlschlegel (2006). PGA4, a GAS homologue
from Candida albicans, is up-regulated early in infection processes. Fungal Genet Biol, in press
Sandherr M, Einsele H, Hebart H, Kahl C, Kern W, Kiehl M, Massenkeil G, Penack O, Schiel X, Schuettrumpf S, Ullmann AJ,
Cornely OA; Infectious Diseases Working Party, German Society for Hematology and Oncology. Antiviral prophylaxis in
patients with haematological malignancies and solid tumours: Guidelines of the Infectious Diseases Working Party
(AGIHO) of the German Society for Hematology and Oncology (DGHO).Ann Oncol. 2006 Jul;17(7):1051-9
Stuhler G, Knop S, Topp MS, Krober SM, Ernemann U, Herrlinger U, Einsele H, Kanz L, Hebart H. Intravenously administered
rituximab induces remission of EBV associated non Hodgkin lymphoma confined to the brain in a patient after allogeneic
stem cell transplantation. Haematologica. 2006 Mar;91(3):ECR01.
T. Berg, M. von Wagner, H. Hinrichsen, C. Sarrazin, T. Heintges, T. Gerlach, P. Buggisch, T. Goeser, J. Rasenack, G. Pape,
W. E. Schmidt, B. Kallinowski, H. Klinker, U. Spengeler, P. Martus, U. Alshuth, S. Zeuzem (2006). Extended Treatment
ZINFbericht-final.P65
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3. Die Institutionen des Zentrums für Infektionsforschung- Publikationen
Duration for Hepatitis C Virus Type 1: A Randomized Trial Comparing 48 versus 72 Weeks of Peginterferon-alfa-2a plus
Ribavirin.Gastroenterology 130: 1086-1097
T. Berg, V. Weich, G. Teuber, H. Klinker, B. Möller, J. rasenack, H. Hinrichsen, G. Pape, U. Spengler, P. Buggisch, M. Zankel,
H.Balk, C. Sarrazin, S. Zeuzem (2006). Individualisierte Therapiestrategie mit Peginterferon alfa-2b (PEG-IFNa) plus
Ribavirin in Abhängigkeit von der frühen Viruskinetik bei Hepatitis C Virus (HCV) Typ 1-infizierten Patienten. Z Gastroenterol
44: 130
T. Weitzel , N. Muhlberger, T. Jelinek, M. Schunk, S. Ehrhardt, C. Bogdan, K. Arasteh, T. Schneider, W. Kern, G. Fatkenheuer,
G. Boecken, T. Zoller, M. Probst, M. Peters T. Weinke, S. Gfrorer, H. Klinker, M. Holthoff-Stich (2005). Surveillance
Importierter Infektionen in Deutschland (SIMPID) Surveillance Network. Imported leishmaniasis in Germany 20012004: data of the SIMPID surveillance network. Eur J Clin Microbiol Infect Dis. 24: 471-476
V. Weich, G. Teuber, C. Sarrazin, H. Klinker, P. Buggisch, E. Schott, A. Bergk, H. Witt, T. Berg (2006). Einfluss des Apolipoprotein
E4 Allels auf das Therapieansprechen mit PEG-IFNa plus Ribavirin mit Hepatitis C Virus (HCV)-Typ 1-Infektion. Z
Gastroenterol 44: 126
Vogel W, Kopp HG, Kanz L, Einsele H.Myeloma cell contamination of peripheral blood stem-cell grafts can predict the
outcome in multiple myeloma patients after high-dose chemotherapy and autologous stem-cell transplantation.J
Cancer Res Clin Oncol. 2005 Apr;131(4):214-8.
W. Heinz, C. Klöser, C. Guhl, A. Helle, H. Einsele, H. Klinker (2006). Surveillance of voriconazole plasma concentrations in
patients with haematological malignancies. Onkologie 29 (Suppl 3): 216-217
3-9 Institute of Neurology, (in the field of Immunology and Infectiology):
Perron H,, Lazarini F, Ruprecht K, Péhoux-Longin C, Seilhean D, Sazdovitch V, Cr•ange A, Battail-Poirot N, Sibai G, Santoro L,
Jolivet M, Darlix JL, Rieckmann P, Arzberger T, Hauw JJ, Lassmann H. (2005) Human endogenous retrovirus (HERV)-W env
and gag proteins: physiological expression in human brain and physiopathological modulation in multiple sclerosis
lesions. J. Neurovirol. 11: 23-33.
Kroner A, Rosche B, Kolb-Mäurer A, Kruse N, Toyka KV, Hemmer B, Rieckmann P, MŠurer M. (2005) Impact of the Asp299Gly
polymorphism in the toll-like receptor 4 (tlr-4) gene on disease course of multiple sclerosis. J. Neuroimmunol. 165: 1615.
Ruprecht K, Obojes K, Wengel V, Gronen F, Kim KS, Perron H, Schneider-Schaulies J, Rieckmann P.(2006) Regulation of
human endogenous retrovirus-W protein expression by herpes simplex virus type 1: Implications for the pathogenesis of
multiple sclerosis. J. Neurovirol. 12; 65-72.
Buttmann M, Berberich-Siebelt F, Serfling E, Rieckmann P. (2007) Interferon-b Is a Potent Inducer of STAT1/2-mediated MCP-1/
CCL2 and of IRF-1/2-dependent IP-10/CXCL10 Chemokine Expression in Primary Human Endothelial Cells J. Vasc. Res.
44: 51-60.
Gronen F, Ruprecht K, Weissbrich B, Klinker E, Hofstetter H, Kroner A, Rieckmann P. (2006)Frequency of HLA-B7-restricted
Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis. J. Neuroimmunol. 180: 185-192
3-10 Children Hospital - Pedriatic Infectiology, (in the field of Immunology and Infectiology):
D’Alquen, D., Kramer, B.W., Seidenspinner, S., Marx, A., Berg, D., Groneck, P., Speer, C.P. (2005) Activation of umbilical cord
endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatr Res 57:
263-269
Girschick, H.J., Raab, P., Surbaum, S., Trusen, A., Kirschner, S., Schneider, P., Papadopoulos, T., Muller-Hermelink, H.K.,
Lipsky, P.E. (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64: 279-285.
Klotz, P., Tappe, D., Abele-Horn, M., Warmuth-Metz, M., Sorensen, N., Speer, C.P., Girschick, H.J. (2006) Cerebral mass in a 13year-old girl following long-term sojourn in the Tropics. J Med Microbiol 55: 345-347.
Kramer, B.W., Kaemmerer, U., Kapp, M., Herbst, D., Marx, A., Berg, D., Groneck, P.A., Speer, C,P. (2005) Decreased expression
of angiogenic factors in placentas with chorioamnionitis after preterm birth. Pediatr Res 58(3):607-612
Koenig, C., Hebestreit, H., Valenza, G., Abele-Horn, M., Speer, C.P. (2005) Legionella waltersii – a novel cause of pneumonia?
Acta Paediatr 94:1505-7
Kunzmann, S., Warmuth-Metz, M., Girschick, H.J. (2005) Cerebral demyelination in association with TNF-inhibition therapy in
a 5-year-old girl with aseptic meningitis as the first symptom of Still’s disease. Scand J Rheumatol 34: 76-78.
Kunzmann, S., Speer, C.P., Jobe, A.H., Kramer, B.W. (2006) Antenatal inflammation induced TGF-â1 but suppressed CTGF in
preterm lungs. Am J Physiol Lung Cell Mol Physiol, in press
Kunzmann, S., Wright, J.R., Steinhilber, W., Kramer, B.W., Blaser, K., Speer, C.P., Schmidt-Weber, C. (2006) TGF-â1 in SP-A
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113
preparations influences immune suppressive properties of SP-A on human CD4+ T lymphocytes. Am J Physiol Lung
Cell Mol Physiol, in press
Maschmann, J., Hamprecht, K., Weissbrich, B., Dietz, K., Jahn, G., Speer, C.P. (2006) Freeze-thawing of breast milk does not
prevent cytomegalovirus transmission to a preterm infant. Arch Dis Child Fetal Neonatal Ed 91:F288-90
Neuberger, P., Hamprecht, K., Vochem, M., Maschmann, J., Speer, C.P., Poets, C.F., Goelz, R. (2006) Case control study of
symptoms and neonatal outcome of human milk-transmitted cytomegalovirus infection in preterm infants. J Pediatr
148(3):326-31
Siauw, C., Kobsar, A., Dornieden, C., Beyrich, C., Schinke, B., Schubert-Unkmeir, A., Abele-Horn, M., Speer, C.P., Eigenthaler, M.
(2006) Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signalling
cascades. Thrombosis and Haemostasis 95(5):836-49
Singh, S.K., Girschick, H.J. (2004a) Molecular survival strategies of the Lyme disease spirochete Borrelia burgdorferi. Lancet
Infect Dis 4: 575-583.
Singh, S.K., Girschick, H.J. (2004b) Lyme borreliosis: from infection to autoimmunity. Clin Microbiol Infect 10: 598-614.
Singh, S.K., Morbach, H., Nanki, T., Faber, C., Baar, V., Girschick, H.J. (2004) Differential expression of matrix metalloproteinases
and cyclooxygenases in synovial cells exposed to Borrelia burgdorferi. Inflamm Res 53: 689-696.
Singh, S.K., Morbach, H., Nanki, T., Girschick, H.J. (2005) Differential expression of chemokines in synovial cells exposed to
different Borrelia burgdorferi isolates. Clin Exp Rheumatol 23: 311-322.
Singh, S.K., Baar, V., Morbach, H., Girschick, H.J. (2006) Expression of ICAM-1, ICAM-2, NCAM-1 and VCAM-1 by human
synovial cells exposed to Borrelia burgdorferi in vitro. Rheumatol Int 26: 818-827.
Singh, S.K., Girschick, H.J. (2006) Toll-like receptors in Borrelia burgdorferi-induced inflammation. Clin Microbiol Infect 12:
705-717.
Sitaru, A.G., Holzhauer, S., Speer, C.P., Singer, D., Obergfell, A., Walter, U., Speer, C.P., Grossmann, R. (2005) Neonatal
platelets: Are they different? Platelets 16:203-210
Sitaru, A.G., Speer, C.P., Holzhauer, S., Obergfell, A., Walter, U., Grossmann, R. (2005) Chorioamnionitis is associated with
increased CD40L expression on cord blood platelets. Thromb Haemost 94(6):1219-23
Speer, C.P. (2006) Pulmonary inflammation and bronchopulmonary dysplasia. J Perinatol 26(1):S57-62.
Speer, C.P. (2006) Inflammation and Bronchopulmonary Dysplasia: A Continuing Story. Sem Fetal Neonat Med 11(5):354-62.
Thomas, W., Speer, C.P. (2005) Best practice guidelines: Management of infants with bronchopulmonary dysplasia in
Germany. Early Human Development 81(2): 155-163
Valenza, G., Burgemeister, S., Girschick, H., Schoen, C., Veihelmann, S., Moter, A., Haban, V., Vogel, U., Schlagenhauf, U.
(2006) Analysis of the periodontal microbiota in childhood-type hypophosphatasia. Int J Med Microbiol.Nov;296(7):493500.
3-11 Department of Skin Diseases and Veneral Diseases (in the field of Immunology and Infectiology):
Andersen MH, Becker JC, Straten P. Regulators of apoptosis: suitable targets for immune therapy of cancer. Nat Rev Drug
Discov. 2005 May;4:399-409.
Andersen MH, Reker S, Kvistborg P, Becker JC, thor Straten P. Spontaneous immunity against Bcl-xL in cancer patients. J
Immunol. 2005 Aug 15;175:2709-14.
Becker JC, Houben R, Vetter CS, Broecker EB. The carcinogenic potential of tacrolimus ointment beyond immune
suppression: a hypothesis creating case report. BMC Cancer.Jan 2006; 11;6:7
Friedl P, den Boer AT, Gunzer M. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat
Rev Immunol. 2005 Jul;5:532-45.
Gesierich A, Herzog S, Grunewald SM, Tappe D, Bröcker EB, Schön MP: Eosinophilic folliculitis in a Caucasian patient:
Association with toxocariasis? J. Eur. Acad. Dermatol. 20, 1317-1321, 2006
Hamm H. Mites, lice and fleas. Ectoparasitoses in infancy and childhood. Hautarzt. 2005 Oct;56:915-24.
Herrero-Gonzalez JE, Sitaru C, Klinker E, Brocker EB, Zillikens D. Successful adjuvant treatment of severe bullous pemphigoid
by tryptophan immunoadsorption. Clin Exp Dermatol. 2005 Sep;30:519-22.
Hofmeister V, Vetter C, Schrama D, Brocker EB, Becker JC. Tumor stroma-associated antigens for anti-cancer immunotherapy.
Cancer Immunol Immunother. 2005 Oct 12:1-14
Hofmeister V, Vetter C, Schrama D, Brocker EB, Becker JC. Tumor stroma-associated antigens for anti-cancer immunotherapy.
Cancer Immunol Immunother. 2005 Oct 12:1-14
Kerstan A, Rose C, Simon D, Simon HU, Brocker EB, Trautmann A, Leverkus M. Bullous delayed pressure urticaria:
pathogenic role for eosinophilic granulocytes? Br J Dermatol. 2005 Aug;153:435-9.
Kerstan A, Schön MP: Viewpoint: Who is really in control of skin immunity under physiological circumstances -–lymphocytes,
dendritic cells, or keratinocytes? Exp. Dermatol.15, 929, 2006
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3. Die Institutionen des Zentrums für Infektionsforschung- Publikationen
Kroner A, Vogel F, Kolb-Maurer A, Kruse N, Toyka KV, Hemmer B, Rieckmann P, Maurer M. Impact of the Asp299Gly
polymorphism in the toll-like receptor 4 (tlr-4) gene on disease course of multiple sclerosis. J Neuroimmunol. 2005
Aug;165:161-5.
Kurzai O, Schmitt C, Brocker E, Frosch M, Kolb-Maurer A. Polymorphism of Candida albicans is a major factor in the
interaction with human dendritic cells. Int J Med Microbiol. 2005 Jun;295:121-7
Kurzai O, Schmitt C, Claus H, Vogel U, Frosch M, Kolb-Maurer A. Carbohydrate composition of meningococcal
lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell Microbiol.
2005 Sep;7:1319-34.
Ludwig RJ, Zollner TM, Santoso S, Hardt K, Gille J, Baatz H, Johann PS, Pfeffer J, Radeke HH, Schon MP, Kaufmann R,
Boehncke WH, Podda M. Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the
skin and mediate cutaneous inflammation. J Invest Dermatol. 2005 Nov;125:969-76.
Ludwig RJ, Zollner TM, Santoso S, Hardt K, Gille J, Baatz H, Schulze Johann P, Pfeffer J, Radeke HH, Schön MP, Kaufmann
R, Boehncke WH, Podda M: Junctional adhesion molecules (JAM)-B and –C contribute to leukocyte extravasation to the
skin and mediate cutaneous inflammation. J. Invest. Dermatol. 125, 969-976, 2005
Otto K, Andersen MH, Eggert A, Keikavoussi P, Pedersen LO, Rath JC, Bock M, Brocker EB, Straten PT, Kampgen E, Becker
JC. Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine. 2005
Jan 4;23:884-9.
Rose E, Wever S, Zilliken D, Linse R, Haustein UF, Brocker EB. Intravenous examethasone-cyclophosphamide pulse
therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a
multicenter prospectively randomized study. J Dtsch Dermatol Ges. 2005 Mar;3:200-6.
Schad SG, Trcka J, Vieths S, Scheurer S, Conti A, Brocker EB, Trautmann A. Wine Anaphylaxis in a German Patient: IgEMediated Allergy against a Lipid Transfer Protein of Grapes. Int Arch Allergy Immunol. 2005 Jan 12;136:159-164
Schmid-Grendelmeier P, Fluckiger S, Disch R, Trautmann A, Wuthrich B, Blaser K, Scheynius A, Crameri R. IgE-mediated
and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis. J Allergy Clin
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Schoen C, Kolb-Maurer A, Geginat G, Loffler D, Bergmann B, Stritzker J, Szalay AA, Pilgrim S, Goebel W. Bacterial delivery of
functional messenger RNA to mammalian cells. Cell Microbiol. 2005 May;7:709-24.
Schön MP, Boehncke WH, Bröcker EB: Psoriasis – clinical manifestations, pathogenesis and therapeutic perspectives.
Discovery Medicine 5, 253-258, 2005
Schön MP, Boehncke WH: Psoriasis. N. Engl. J. Med. 352, 1899-1912, 2005
Schon MP, Ludwig RJ. Lymphocyte trafficking to inflamed skin—molecular mechanisms and implications for therapeutic
target molecules. Expert Opin Ther Targets. 2005 Apr;9:225-43.
Schön MP, Schön M, Klotz KN: The small anti-tumoral immune response modifier imiquimod interacts with adenosine
receptor signaling in a TLR7- and 8-independent fashion. J. Invest. Dermatol. 126, 1338-1347, 2006
Schön MP, Schön M: The small-molecule immune response modifier imiquimod – Its mode of action and clinical use in the
treatment of skin cancer. Expert Opin. Ther. Targets 10; 69-76, 2006
Schön MP: Advances in psoriasis treatment. Lancet 366, 1333-1335, 2005
Schön MP: Inhibitors of selectin functions in the treatment of inflammatory skin disorders. Therapeutics Clin. Risk.
Management, 1, 201-208, 2005
Schön MP: Leukocyte extravasation as a target for anti-inflammatory therapy – which molecule to choose? Exp. Dermatol.
14, 74-76, 2005
Schrama D, Terheyden P, Otto K, Kammerer U, Brocker EB, Luhder F, Cosman D, Andersen MH, Becker JC. Expression of
the NKG2D ligand UL16 binding protein-1 (ULBP-1) on dendritic cells. Eur J Immunol. Jan 2006;36:65-72
Schubert B, Grosse Perdekamp MT, Pfeuffer P, Raith P, Brocker EB, Trautmann A. Nonsteroidal anti-inflammatory drug
hypersensitivity: fable or reality? Eur J Dermatol. 2005 May-Jun;15:164-7.
Siegmund D, Wicovsky A, Schmitz I, Schulze-Osthoff K, Kreuz S, Leverkus M, Dittrich-Breiholz O, Kracht M, Wajant H. Death
receptor-induced signaling pathways are differentially regulated by gamma interferon upstream of caspase 8 processing.
Mol Cell Biol. 2005 Aug;25:6363-79.
Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, Krenn V, Schön MP, Scheffold A, Lowe JB, Hamann A,
Syrbe U, Huehn J: Migration matters: regulatory T cell compartmentalization determines suppressive activity in vivo.
Blood 106, 3097-3104, Nov 2005
Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, Krenn V, Schön MP, Scheffold A, Lowe JB, Hamann A,
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Blood 106, 3097-3104, 2005
Straten PT, Dahl C, Schrama D, Pedersen LO, Andersen MH, Seremet T, Brocker EB, Guldberg P, Becker JC. Identification
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3. Institutions of the Research Center for Infectious Diseases - Publications
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Trautmann A, Kruger K, Akdis M, Muller-Wening D, Akkaya A, Brocker EB, Blaser K, Akdis CA. Apoptosis and loss of adhesion
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Trujillo-Vargas CM, Ramirez-Pineda JR, Palmetshofer A, Grunewald S, Moll H, Berberich C, Erb KJ. Mice vaccinated with
allergen-pulsed myeloid dendritic cells are not protected from developing allergen-induced Th2 responses. Int Arch
Allergy Immunol. 2005 Jul;137:219-28.
Vassina E, Leverkus M, Yousefi S, Braathen LR, Simon HU, Simon D. Increased expression and a potential anti-inflammatory
role of TRAIL in atopic dermatitis. J Invest Dermatol. 2005 Oct;125:746-52.
Voigt H, Schrama D, Eggert AO, Vetter CS, Muller-Blech K, Reichardt HM, Andersen MH, Becker JC, Luhder F. CD28mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin Exp Immunol.
2006 Jan;143:93-102.
Voigt H, Schrama D, Eggert AO, Vetter CS, Muller-Blech K, Reichardt HM, Andersen MH, Becker JC, Luhder F. CD28mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin Exp Immunol.
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Waschke J, Bruggeman P, Baumgartner W, Zillikens D, Drenckhahn D. Pemphigus foliaceus IgG causes dissociation of
desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction. J Clin Invest. 2005 Nov;115:315765.
Weyandt GH, Benoit S, Becker JC, Brocker EB, Hamm H. Controlled layered removal of anogenital warts by argon-plasma
coagulation. J Dtsch Dermatol Ges. 2005 Apr;3:271-5.
Wienrich BG, Krahn T, Schön M, Rodriguez ML, Kramer B, Busemann M, Boehncke WH, Schön MP: Structure-function
relation of efomycines, a family of small-molecule inhibitors of selectin functions. J. Invest. Dermatol. 126, 882-889,
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3-12 Surgical Clinic with Out-patients' Department (in the field of Infectiology):
Lorenz, U; Ohlsen, K; Karch, H; Hecker, M; Thiede, A; Hacker, J. Human antibody response during sepsis against targets
expressed by methicillin resistant Staphylococcus aureus. FEMS Immunol Med Microbiol 2000 29(2):145-53.
Lorenz, U; Ohlsen, K; Karch, H; Thiede, A; Hacker, J. Immunodominant proteins in human sepsis caused by methicillin
resistant Staphylococcus aureus. Adv Exp Med Biol 2000;485:273-8.
Lorenz, U; Hüttinger, C; Ziebuhr, W; Würzler, C; Thiede, A; Hacker, J; and Ohlsen, K. The alternative sigma factor sigma B of
Staphylococcus aureus is crucial for the development of infection in a clinical model of sepsis Infection and Immunity,
2007, submitted
Lorenz U, Hüttinger C, Wehland J, Werner B, Schäfer T, Thiede A, Hacker J and Ohlsen K. Therapeutic activity of a novel
monoclonal antibody (MAB-ISAA29) against Staphylococcus aureus J Exp Med 2007, submitted
3-13 Department of Tropical Medicine at the Medicinical Misso Hospital:
Abdel-Aziz, I.Z., Oster, N., Stich, A., Coulibaly, B., Guigemde, W.A., Wickert, H., Andrews, K.T., Kouyate, B., and Lanzer, M. (2005)
Association of Plasmodium falciparum isolates encoding the p. Falciparum chloroquine resistance transporter gene
K76T polymorphism with anemia and splenomegaly, but not with multiple infections. Am J Trop Med Hyg 72: 252-255.
Agranoff, D., Stich, A., Abel, P., and Krishna, S. (2005) Proteomic fingerprinting for the diagnosis of human African trypanosomiasis.
Trends Parasitol 21: 154-157.
Inojosa, W.O., Augusto, I., Bisoffi, Z., Josenado, T., Abel, P.M., Stich, A., and Whitty, C.J. (2006) Diagnosing human African
trypanosomiasis in Angola using a card agglutination test: observational study of active and passive case finding strategies.
Bmj 332: 1479.
Oster, N., Abdel-Aziz, I.Z., Stich, A., Coulibaly, B., Kouyate, B., Andrews, K.T., McLean, J.E., and Lanzer, M. (2005) Comparison of
different PCR protocols for the detection and diagnosis of Plasmodium falciparum. Parasitol Res 97: 424-428.
Schmidt, E., Weissbrich, B., Brocker, E.B., Fleischer, K., Goebeler, M., and Stich, A. (2006) Orf followed by erythema multiforme.
J Eur Acad Dermatol Venereol 20: 612-613.
Stich, A., Oster, N., Abdel-Aziz, I.Z., Stieglbauer, G., Coulibaly, B., Wickert, H., McLean, J., Kouyate, B.A., Becher, H., and Lanzer,
M. (2006) Malaria in a holoendemic area of Burkina Faso: a cross-sectional study. Parasitol Res 98: 596-599.
Tappe, D., Winzer, R., Buttner, D.W., Strobel, P., Stich, A., Klinker, H., and Frosch, M. (2006) Linguatuliasis in Germany. Emerg
Infect Dis 12: 1034-1036.
Vicik, R., Hoerr, V., Glaser, M., Schultheis, M., Hansell, E., McKerrow, J.H., Holzgrabe, U., Caffrey, C.R., Ponte-Sucre, A., Moll, H.,
Stich, A., and Schirmeister, T. (2006) Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg Med Chem Lett 16: 2753-2757.
Weinke, T., Liebold, I., Burchard, G.D., Fruhwein, N., Grobusch, M.P., Hatz, C., Kollaritsch, H., Nothdurft, H.D., Reisinger, E.,
Rieke, B., Schonfeld, C., Steffen, R., and Stich, A. (2006) [Prophylactic immunization against enterotoxin-forming Escherichia
coli travellers’ diarrhea and cholera: does it make sense and for whom?]. Dtsch Med Wochenschr 131: 1660-1664.
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