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Einfluß von Infektionserregern auf die Ergebnisse von
Tierversuchen
Implication of infectious
agents on results of animal experiments
Es ist unbestritten, daß sich Infektionserreger
bei Versuchstieren nicht nur auf die Gesundheit
von Tieren (und Menschen) auswirken, sondern
auch massiv Ergebnisse von Tierexperimenten
beeinflussen können. Einer mikrobiologischen
Standardisierung von Versuchstieren kommt daher ganz erhebliche Bedeutung zu.
It is generally accepted that rodent pathogens
may not only be hazardous for animals (and humans) but can severely influence results of animal experiments. Microbiological standardisation of laboratory animals is therefore of crucial
importance.
Es ist schon seit langer Zeit bekannt, daß Mikroorganismen vielfältige Einflüsse auf ihren
Wirt ausüben können. Schon früh wurden solche Einflüsse beispielsweise auf Entwicklung
und Wachstum von Tumoren beobachtet. So
konnte gezeigt werden, daß keimfreie Mäuse
nach Behandlung mit chemischen Karzinogenen
weniger Tumoren (Lunge, Leber, Mamma, Uterus, Ovar) entwickeln als konventionell gehaltene Mäuse (Burstein et al. 1970, Roe and Grant
1970, Schreiber et al. 1972). Die Bedeutung von
Mikroorganismen als Einflußgrößen für Experimente wurde schon vor mehr als 25 Jahren in
Übersichtsarbeiten beschrieben (van der Waaij
and van Bekkum 1967, Hanna et al. 1973, Baker et al. 1979). Bereits 1971 wurde ein Symposium zu dieser Problematik abgehalten (Pakes
and Benirschke 1971), und damals bekannte
Einflüsse ausgewählter Erreger wurden anschließend publiziert.
Bedeutung von Infektionserregern:
Erreger können sich auf vielfältige Weise auf
Tierpopulationen auswirken. Einige Mikroorganismen besitzen pathogene Eigenschaften und
können klinische Symptome mit unterschiedlicher Morbiditäts- oder Mortalitätrate hervorrufen. Die meisten Erreger verursachen allerdings,
zumindest bei endemischem Verlauf, keine oder
sehr mild verlaufende Erkrankungen. Teilweise
kommt es zu Ausfällen infolge von Todesfällen
oder Krankheit. In vielen Fällen wird das Auftreten von Symptomen gefördert durch Belastungen oder Streß, die durch das Experiment
verursacht werden. Häufig sind bestimmte
Stämme einer Tierart anfälliger, bei anderen
Stämmen verläuft dieselbe Infektion milder, mit
anderen Symptomen, oder gar ohne klinische
Anzeichen einer Infektion. Besonders bei immundefizienten Tieren sind stärkere Auswirkungen zu erwarten. Oft kommt es ohne akute An-
It has been known for decades that microorganisms may have impact on their hosts in various ways. Many years ago, influences of microorganisms were detected on development
and growth of tumours. It was shown by various authors that germ-free mice develop fewer tumours (lung, liver, mamma, uterus, ovary) after treatment with chemical carcinogens
than conventionally housed animals (Burstein
et al. 1970, Roe and Grant 1970, Schreiber et
al. 1972). The importance of microorganisms as
factors that may influence animal experiments
has already been described in review articles
more than 25 years ago (van der Waaij and van
Bekkum 1967, Hanna et al. 1973, Baker et al.
1979). A first symposium dealing with this issue was held in 1971, and hitherto known influences of selected microorganisms were published afterwards (Pakes and Benirschke 1971).
Importance of microorganisms:
Infectious agents may affect animal populations
in various ways. Some are pathogenic and may
induce clinical signs with variable morbidity or
mortality. However, most microorganisms induce no or only mild disease, at least in cases of
endemic infections. Occasionally, loss of animals occurs as a consequence of disease or death. Silent infections are often activated by experimental procedures (stress, immunosuppression, toxic substances, tumours) or environmental influences (transportation, suboptimal humidity or temperature). Frequently, certain strains
of a given species are more sensitive to an infection, whereas the same agent may cause milder or different symptoms in other strains, or
the infection may be asymptomatic. Clinical
signs are usually more serious in immunodeficient animals. Frequently, infections result in a
reduced life expectancy in absence of specific
zeichen einer Infektion nur zu einer reduzierten
Lebenserwartung einzelner Individuen oder
ganzer Populationen. Andere Erreger verursachen Infektionen, die völlig symptomlos verlaufen und selbst bei experimenteller Infektion
nicht zu klinischen Erkrankungen führen.
Unabhängig von ihren pathogenen Eigenschaften können sich viele Erreger jedoch auf die
Physiologie der Tiere und damit auf die Ergebnisse von Tierversuchen auswirken. Daneben
können Infektionen, auch wenn sie asymptomatisch verlaufen, die interindividuelle Variabilität
erhöhen. Dadurch werden erhöhte Tierzahlen
zur Durchführung aussagekräftiger Experimente
notwendig. Direkte Auswirkungen von Erregern
auf Versuchsergebnisse können zu Fehlinterpretationen von Ergebnissen führen und somit dafür verantwortlich sein, daß Experimente nicht
reproduzierbar sind.
Die Verwendung von Tieren, die frei sind von
unerwünschten Mikroorganismen, ist eine wichtige Voraussetzung für die Durchführung von
aussagekräftigen und reproduzierbaren Experimenten mit einem Minimum an Tieren und stellt
somit einen wesentlichen Beitrag zum Tierschutz dar.
Es ist einsichtig, daß experimentelle Daten, die
an klinisch kranken Tieren gewonnen wurden,
nur mit größter Vorsicht verwertet werden dürfen. Aber gerade Erreger, die klinisch unauffällige Infektionen verursachen, können sich fatal
auswirken, weil sie häufig unerkannt bleiben
und somit verfälschte Ergebnisse erhalten und
publiziert werden.
Das Fehlen klinischer Symptome ist diagnostisch völlig wertlos. Das Freisein von unerwünschten Mikroorganismen und damit die Eignung für spezifische Experimente kann nur
durch umfassende mikrobiologische Untersuchungen vor und während des Experiments gewährleistet werden. Die Ergebnisse mikrobiologischer Untersuchungen müssen deshalb bei der
Interpretation eines Experimentes sowohl vom
Experimentator als auch dem Leser einer Publikation zusammen mit den Versuchsdaten berücksichtigt werden. Es sollte daher selbstverständlich sein, daß die Ergebnisse mikrobiologischer Qualitätskontrollen bei Versuchstieren
in einer wissenschaftlichen Publikation enthalten sind (Working Committee for the Biological
Characterization of Laboratory Animals / GVSOLAS 1985). Empfehlungen zur Durchführung mikrobiologischer Untersuchungen bei
disease for some individuals or a whole population. Other agents induce silent infections
which are asymptomatic even in the case of experimental inoculation.
Many agents may have impact on physiologic
parameters and thus on the results of animal experiments independent from their pathogenic
potential. Further, infections may increase interindividual variability. This may result in increased numbers of animals necessary to achieve significant results. Direct effects of infectious agents on experiments may lead to false
conclusions or misinterpretation and may be responsible for lacking reproducibility.
The use of laboratory animals that are free from
unwanted microorganisms is an important prerequisite to achieve reliable and reproducible
results with a minimum of animals and is therefore a significant contribution to animal welfare.
It is obvious that experimental data obtained
from diseased animals should, if ever, be used
only with maximal precaution. However, the effect of clinically silent infections may also be
devastating because they often remain undetected, and thus modified results may be obtained
and published.
The absence of clinical manifestations has no
diagnostic value. The presence of unwanted microorganisms and the suitability of an animal
population for a specific experiment can only
be demonstrated by comprehensive health monitoring before and during experimentation.
Health monitoring data are part of the experimental work and have to be considered during
interpretation of experimental results by the experimentator and by the reader of a publication.
It should, therefore, be self-evident that results
of health monitoring are included in scientific
publications (Working Committee for the Biological Characterisation of Laboratory Animals
/ GV-SOLAS 1985). Recommendations for health monitoring of laboratory animals have
been published repeatedly (Lussier 1991, National Research Council 1991, Kunstyr 1992,
Kraft et al. 1994, Nicklas 1996, Rehbinder et al.
1996, Rehbinder et al. 1998).
Many agents do not only have impact on animals or animal experiments. Numerous organisms are known to affect experiments conducted with isolated organs or cells. Microorganisms may even persist in cells, tumours or
Versuchstieren wurden wiederholt publiziert
(Lussier 1991, National Research Council 1991,
Kunstyr 1992, Kraft et al. 1994, Nicklas 1996,
Rehbinder et al. 1996, Rehbinder et al. 1998).
Viele Erreger wirken sich nicht nur auf Tiere
und die mit ihnen durchgeführten Tierversuche
aus. Von einer Vielzahl Mikroorganismen ist bekannt, daß sie auch Experimente an isolierten
Zellen oder Organen beeinflussen und sogar in
Zellen, Tumoren oder anderen biologischen Materialien für unbestimmte Zeit persistieren können. Mikroorganismen von Versuchstieren können sich somit auch auf Experimente auswirken,
die unter in vitro-Bedingungen durchgeführt
werden. Daneben finden sich Infektionserreger
als Kontaminanten von biologischen Materialien, die von Tieren stammen oder in Tieren passagiert wurden (Tumoren, Seren, Zellen, Viren,
Parasiten). Sie können massiv Einfluß auf Experimente nehmen, die mit solchen Materialien
durchgeführt werden, oder aber über solche Materialien in Versuchstierhaltungen eingeschleppt
werden (Collins and Parker 1976, Nicklas et al.
1993).
Leider werden solche Auswirkungen von Erregern auf Experimente in der Mehrzahl aller Fälle als Artefakte verworfen und nur in Ausnahmefällen publiziert. Informationen über Beeinflussung von Experimenten durch Infektionserreger finden sich in der Literatur deshalb nur
vereinzelt. Mit dieser Zusammenstellung soll
versucht werden, einen Überblick über publizierte Einflüsse einzelner Mikroorganismen auf
Tiere sowie Auswirkungen auf Experimente zu
geben.
other biological materials for unlimited periods
of time and therefore influence in vitro experiments. Furthermore, microorganisms resulting
from a natural infection might contaminate biological materials (tumours, sera, cells, viruses,
parasites) that originate from or have been passaged in infected animals. They may severely
influence experiments conducted with such materials, or may be introduced into animal facilities by contaminated samples (Collins and Parker 1976, Nicklas et al. 1993).
Unfortunately, research complications due to infectious agents are usually considered artefacts
and published only rarely. Information on influences of microorganisms on experiments is scattered in diverse scientific journals, and many articles are difficult to detect. This text therefore
aims at giving an overview on published influences of selected microorganisms on animals as
well as on experiments.
To address the problem, several meetings were
held on viral complications on research. The
knowledge available was summarised in conference proceedings (Melby and Balk 1983, Bhatt
et al. 1986, Hamm 1986) and has later repeatedly been reviewed (Kraft 1985, Lussier 1988,
National Research Council 1991, Hansen 1994,
Mossmann et al. 1998, Baker 1998).
Das Problem der Beeinflussung von Tierversuchen durch Infektionserreger war Mitte der 80iger Jahre Gegenstand mehrerer Kongresse, und
das verfügbare Wissen zu dieser Thematik wurde wiederholt in Proceedings publiziert (Melby
and Balk 1983, Bhatt et al. 1986, Hamm 1986).
Auch danach wurde die Problematik wiederholt
in Übersichtsartikeln zusammengefaßt (Kraft
1985, Lussier 1988, National Research Council
1991, Hansen 1994, Mossmann et al. 1998, Baker 1998).
Ziel dieser Arbeit:
Aim of this compilation:
In Versuchstierhaltungen taucht beim Nachweis
eines Erregers häufig die Frage auf, ob bzw. inwieweit sich dieser Erreger auf Experimente
auswirken kann. Experimentatoren und Ver-
After detection of an organism in an animal facility the question frequently arises if and how
an animal experiment might be influenced. Experimentators and laboratory animal specialists
must in such cases be able to evaluate the im-
suchstierkundler müssen in solchen Fällen die
Bedeutung einer Infektion auf Experimente abschätzen können. Die vorliegende Zusammenstellung soll dabei behilflich sein, indem sie
kurz und übersichtlich für die wichtigeren und
häufiger zu erwartenden Keime publizierte Auswirkungen zusammenstellt und die jeweiligen
Literaturzitate auflistet. Aber auch andere Fragen, die im Zusammenhang mit Infektionen in
Versuchstierpopulationen auftauchen, sollen
hier beantwortet werden (z. B. Zoonoserisiko,
Wirtsspezifität).
Schließlich soll mit dieser Zusammenstellung
auch Leitern von Versuchstierhaltungen eine Argumentationshilfe zur Hand gegeben werden,
um besser und gezielt auf die Verwendung mikrobiologisch standardisierter Tiere und damit
die Durchführung von aussagekräftigeren Experimenten hinzuwirken.
Die Mehrzahl der heute verwendeten Versuchstiere sind Ratten und Mäuse. Gleichzeitig liegen
auch für Nagerkeime die meisten publizierten
Erkenntnisse vor. Diese Zusammenstellung konzentriert sich deshalb auf Mikroorganismen, die
bei Nagern vorkommen, obwohl auch bei anderen Tierarten der Trend zu mikrobiologisch standardisierten Tieren geht (Rehbinder et al. 1998).
Literatur:
Baker, D. G. 1998. Natural pathogens of laboratory mice, rats, and rabbits and their effects on
research. Clin. Microbiol. Rev. 11:231-266
Baker, H. J., J. R. Lindsey, and S. H. Weisbroth.
1979. Housing to control research variables. In:
Baker, H. J., J. R. Lindsey, S. H. Weisbroth
(Eds.).The laboratory rat. Vol. 1 Biology and diseases. p. 167-192. Academic Press, New York.
Bhatt, P.N., R. O. Jacoby, H. C. Morse, and A.
New (Eds.). 1986. Viral and mycoplasmal infections of laboratory rodents: Effects on biomedical research. Academic Press, New York.
Burstein, N. A., K. R. McIntire, and A. C. Allison. 1970. Pulmonary tumors in germfree mice:
induction with urethan. J. Natl. Cancer Inst.
44:211-214.
Collins, M. J., and J. C. Parker. 1972. Murine
virus contamination of leukemia viruses and
transplantable tumors. J. Natl. Cancer Inst.
49:1139-1143.
portance of an infection on research. It is the purpose of this compilation to aid in evaluating the
importance of the most relevant microorganisms
for animal experiments. Published influences of
microorganisms on physiological parameters of
laboratory animals were listed concisely, and the
references are cited. In addition, few other questions which often arise together with infections in
populations of experimental animals are addressed
(e. g., zoonotic potential, host specificity).
Furthermore, it is the aim of this study to support
managers of animal facilities in arguing towards
improved microbiological standardisation of laboratory animals which will result in better and more
reliable results of animal experiments with fewer
animals.
The majority of laboratory animals are mice and
rats, and most information is available for microorganisms infecting these species. This compilation therefore focuses on rodent microorganisms
although there is a general trend towards better
microbiological quality also for other animal species (Rehbinder et al. 1998).
References:
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Baker, H. J., J. R. Lindsey, and S. H. Weisbroth.
1979. Housing to control research variables. In:
Baker, H. J., J. R. Lindsey, S. H. Weisbroth
(Eds.).The laboratory rat. Vol. 1 Biology and diseases. p. 167-192. Academic Press, New York.
Bhatt, P.N., R. O. Jacoby, H. C. Morse, and A.
New (Eds.). 1986. Viral and mycoplasmal infections of laboratory rodents: Effects on biomedical
research. Academic Press, New York.
Burstein, N. A., K. R. McIntire, and A. C. Allison.
1970. Pulmonary tumors in germfree mice: induction with urethan. J. Natl. Cancer Inst. 44:211214.
Collins, M. J., and J. C. Parker. 1972. Murine virus contamination of leukemia viruses and transplantable tumors. J. Natl. Cancer Inst. 49:11391143.
Hamm, T. E. (Ed.). 1986. Complications of viral
and mycoplasmal infections in rodents to toxicology research and testing. Hemisphere Publ.
Co., Washington D. C.
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R. W. Tennant. 1973. The variable influence of
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R. W. Tennant. 1973. The variable influence of
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125-153, CRC Press Inc., Boca Raton.
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G. Milite, J. R. Needham, W. Nicklas, A. Perrot,
C. Rehbinder, and Y. Richard. 1994. Recommendations for the health monitoring of mouse, rat,
hamster, guineapig and rabbit breeding colonies.
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and the environment in biomedical research.
Academic Press, INC., Orlando.
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(Ed.). Methods in Microbiology, Vol. 25. p. 109186, Academic Press Ltd., London.
National Research Council, Committee on Infectious Diseases of Mice and Rats. 1991. Infectious Diseases of mice and rats. National Academy Press, Washington, D. C.
Kunstyr, I. (Ed.). 1992. Diagnostic microbiology
for laboratory animals. GV-SOLAS Vol. 11. Gustav Fischer Verlag, Stuttgart.
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rodent viral infections on long-term experiments.
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MINUTE VIRUS OF MICE (MVM)
Host species
• natural host: laboratory and wild mice (Parker et al. 1970, Singleton et al. 1993,
Smith et al. 1993)
• hamsters and rats are susceptible to experimental infection (Kilham and Margolis
1970, 1971)
Properties of the Virus
• highly temperature resistant (Fassolitis et al. 1985)
• highly resistant to environmental conditions like e.g. desiccation (Tattersall & Cotmore 1986, National Research Council 1991)
• like other parvoviruses, MVM can infect cells only during the S phase of the mitotic
cycle (Tattersall 1972)
• two allotropic variants exist which replicate in fibroblasts (MVMp) or in T lymphocytes (MVMi) (McMaster et al. 1981, Spalholz and Tattersall 1983, Antonietti
et al. 1988, Gardiner and Tattersall 1988)
• Oncogenic transformation of cells by radiation, chemical carcinogens, or SV40 increases permissiveness to MVMp (Cornelis et al. 1988a).
• transplacental transmission after experimental infection of pregnant hamsters,
mice and rats (Kilham and Margolis 1971)
•mouse embryos with intact zona pellucida are not susceptible to infection (Mohanty
and Bachmann 1974)
Strain susceptibility
• the host strain may influence the mode and extend of horizontal transmission (Tattersall & Cotmore 1986)
• three susceptibility phenotypes in response to MVMi: asymptomatic infection in
C57BL/6, lethal with intestinal haemorrhage in DBA/2, lethal with renal haemorrhage in BALB/c, C3H and other strains (Brownstein et al. 1991)
• amount of viral DNA produced during infection is dependent on host strain (Kapil
1995)
Organotropism
• viral replication only in mitotically active tissues like, e.g. embryos (Tattersall &
Cotmore 1986)
• benign foetal infections in mice (Kilham and Margolis 1975)
• MVMi causes generalised infection of endothelium, lymphocytes, and haematopoietic cells and produces bilateral infarcts of the renal papilli (Brownstein et al. 1991)
Clinical disease
• natural infection of mice usually asymptomatic (Ward and Tattersall 1982, National Research Council 1991, Jacoby et al. 1996)
• subclinical infection in experimentally infected rats or mice and lethal disease in
hamsters after experimental infection (Kiham & Margolis 1970)
• infectivity, organotropism, and pathogenesis of infection is dependent on characteristics of the virus (Brownstein et al. 1992, Jacoby & Ball-Goodrich 1995)
• growth retardation of mice after experimental infection (Kilham and Margolis
1970)
• MVMi but not MVMp is able to induce a runting syndrome in experimentally infected new-born mice (Kimsey et al. 1986)
• foetal death and resorption (Kilham and Margolis 1971)
• periodontal disease and mongolism in hamsters surviving experimental infection
(Kilham and Margolis 1970)
Pathology
• intranuclear inclusions in some infected animals (Kilham and Margolis 1971)
• no pathological lesions after natural infection (National Research Council 1991)
Morbidity and mortality
• MVMi more pathogenic for mice than MVMp, MVMi influences growth of mice
shortly infected after birth, some die of the infection; non pathogenic in adult mice
(Kimsey et al. 1986)
• pathogenic in foetal hamsters and rats, no clinical disease in experimentally infeced mothers (Kilham and Margolis 1971)
Zoonotic potential
• none
Interference with research
Pathology
• intranuclear inclusion bodies (Kilham and Margolis 1971)
• dental defects in aged hamsters after infection at 5 days of age (Baer and Kilham
1974)
Immunology
• weak induction of interferon in vivo (Harris et al. 1974) and of IFN-b, TNFa and IL6 in vitro (Schlehofer et al. 1992)
• strong inhibitory effects of the immunosuppressive variant (MVMi) on allogeneic
mixed lymphocyte cultures in vitro (Bonnard et al. 1976)
• inhibition of lymphocyte proliferation and the generation of cytolytic T lymphocyte
activity but not interferon production, inhibition of growth and cytolytic activity of
T cell lines, suppression of an in vitro antibody response by MVMi but not by
MVMp (Engers et al. 1981)
• inhibition of the generation of cytolytic T lymphocytes by MVMi (McMaster et al.
1981)
• reduction of T cell mitogenic responses and interference with helper dependent B
cell responses in vitro (Tattersall and Cotmore 1986)
• depression of splenic T cell and B cell mitogenic stimulation in vivo (Tattersall and
Cotmore 1986)
• neonatal infections by MVMi may have long-term effects on immunocompetence
(Kimsey et al. 1986)
• inhibition of haematopoiesis in vitro by MVMi but not by MVMp (Segovia et al.
1991, Bueren et al. 1991)
• decreased haematopoiesis in spleen and bone marrow cells (Segovia et al. 1995)
Physiology
• degeneration of the lens and the adjacent retinal layers after infection of new-born
hamsters, extensive hypertrophy of the Harderian glands (Toolan 1983)
Cell biology
• contaminant of cell lines, leukemias, and transplantable tumours (Parker et al.
1970, Collins and Parker 1972, Zoletto 1985, Garnick 1996, Chang et al. 1997)
• persistent infection of cell lines (Ron & Tal 1985, Koering, C. E., et al. 1996)
• disruption of nucleolar functions by virus replication in the nucleolus (Walton et al.
1989)
• interference of a virus protein (NS1) with cell DNA replication, cell cycle stops in
the S phase (op de Beeck & Caillet-Fauquet 1997)
• viral DNA replication in fibroblasts co-infected with MVM and adenovirus is markedly dependent on the cell line (Fox et al. 1990)
Teratology
• congenital malformation (Margolis & Kilham 1975)
• death and resorption of foetuses (Kilham & Margolis 1971, Jordan & Sever 1994)
Infectiology
• first described as a contaminant of a stock of mouse adenovirus (Crawford 1966)
Oncology
• contamination of transplantable or chemically induced tumours (Parker et al. 1970,
Collins & Parker 1972, Bonnard et al. 1976, Lussier 1991, Nicklas et al. 1993)
• inhibition of cell transformation by SV40 (Mousset & Rommelaere 1982)
• stable transformed phenotype is required for complete competence for MVM replication (Rommelaere & Tatersall 1990)
• greater susceptibility of human oncogenic transformed cells and tumour-derived
cell lines than of normal untransformed parental cells (Mousset et al. 1986, Cornelis et al. 1988a, Rommelaere & Cornelis 1991)
• cultures of transformed rat fibroblasts are more susceptible to the cytopathic effect
of MVMp than their untransformed homologues (Cornelis et al. 1988b, Guetta et
al. 1990)
•suppression of Ehrlich ascites tumours in mice after coinjection of MVM and acquisition of long-term resistance to additional injections of tumour cells (Guetta et al.
1986)
•both strains suppress growth of p815 mastocytoma in mice concurrently infected
(Kimsey et al. 1986)
• oncogenes from different functional classes cooperate in the responsiveness of cells
to attack by MVMp (Legrand et al. 1992)
• cooperation of virus proteins (NS1) with oncogenes results in cell death (Mousset et
al. 1994)
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Author: Werner Nicklas, DKFZ Heidelberg, Germany
Theiler`s murine encephalomyelitis virus
Host species
• natural hosts: wild mice [1], laboratory mice, [2] [3] [4], water, bank and meadow
voles (family Microtinae) [5] [6]
• positive serological reactions in laboratory rats [7] [8]; virus might be related to
TMEV-virus, only one report on clinical signs and lesions in rats (MHG-strain) [9],
positive serological findings may indicate the presence of a yet uncharacterised virus (?rat cardiovirus?) [10]
• guinea pigs: the presence of antibodies to TMEV in guinea pigs suffering from lameness indicates that the causative agent of guinea pig lameness might be a cardiovirus [11]
• mice, rats, hamsters and cotton rats are susceptible to intracerebrally inoculated
virus (GDVII strain) but not guinea pigs [12] [13].
Serological prevalence of TMEV in mouse and rat colonies:
Canada: 1980/1986: 40% of mouse colonies, 58% of rat colonies [8]
Germany: 1987-1988: 11% of mouse colonies, 20% of rat colonies [3]
France: 1996/1997: 26% of mouse colonies, 13% of rat colonies [2]
United States: 1996: 30% of mouse colonies, 5-10% of rat colonies [14]
Properties of the Virus
RNA-virus, family Picornaviridae, Genus Cardiovirus; all TMEV strains (see below) are of
the same serotype and cross-neutralize with polyclonal antisera [15] [16].
• different subgroups exist:
•subgroup TO (DA, BeAn 8386, WW, TO, Yale) may produce chronic persistent
infection of the CNS, accompanied by demyelinating lesions of the spinal cord;
small plaques in cell culture;
• subgroup GDVII (FA, GDVII) produce acute fulminant encephalomyelitis; large
plaques in cell culture [17] [18];
• virus can be stored for a long period at –60°C
• optimal stability of the virus in the vicinity of pH 8 and pH 3,3
• exposure to air has little influence on the stability of the virus
• TMEV is rapidly destroyed at temperatures above 50°C
• virus is completely inactivated by 1% H2O2 at 37°C and by 50% acetone or alcohol
[19].
Strain susceptibility
different susceptibilities of various mouse strains after experimental intracerebral inoculation [17] [20]:
• high susceptibility: SJL/J, DBA/1, DBA/2, SWR, PL/J and NZW mice
• intermediate susceptibility: C3H, CBA, AKR, C57BR mice
• resistant: BALB/C substrains, C57BL/6, C57BL/10, C57/L, 129/Jm and H-2D(b)
mice; resistance to DA-virus in H-2(b) mice maps to the H-2D gene and is associated with a potent antiviral cytotoxic T-lymphocyte response [21]
• with cyclophosphamide (cy), mice can be made susceptible but resistance was restored by adoptive transfer of splenic cells from non cy treated donors, only C57Bl/6
could not be made susceptible; high doses of gamma irradiation increase susceptibility of mice [20]
Organotropism
replication of the virus in gastrointestinal mucosa [22] [23]; natural infection rarely spreads from intestine to spinal cord or brain; macrophages are a reservoir of the virus (Da, To,
WW, BeAn) [24] [25] as well as oligodendrocytes, astrocytes and microglia [26] [27]; placentas and foetuses (only in early gestation) can be infected [28];
Clinical disease
• mice, natural infection, subgroup TO (DA, BeAn 8386, WW, TO, Yale): in
mice asymptomatic gastrointestinal infection (except immunodeficient mice [29]),
the virus rarely spreads to the central nervous system [30] [13], symptoms are flaccid posterior paralysis and seldom anterior paralysis in mice that are otherwise clinically normal; incubation period: 7-30 days
• mice, natural infection, subgroup GDVII (FA, GDVII): encephalomyelitic form
may be expressed clinically by excitability, circling, rolling, tremor and convulsions
on noise stimulation (incubation time: 2-9 days); most of the infected mice die soon
after onset of clinical signs [23]
• Rats, MHG-virus strain: case report of symptoms in 3 rats of a colony with symptoms like circling, incoordination, tremor, torticollis [9]
• experimental infections in mice and rats (intracerebrally, intranasally or
footpad inoculation): strains DA, BeAn, WW, TO, Yale: wobbling gait, about 2
to 4 weeks p.i., followed by weakness of the posterior limbs, spastic paralysis,
urinary incontinence and priapism [31] [32]; weanling rats die within 2-3 days without paralytic symptoms [12] strains FA, GDVII: hyperexcitability, circling, and
flaccid paralysis which lead to death within one week [23] [33] [34]
Pathology
• mice, natural infection, subgroup TO (DA, BeAn 8386, WW, TO, Yale): nonsuppurative encephalomyelitis with gliosis and necrosis of ventral horn neurons of
the spinal cord and neuronal necrosis in posterior regions of the brain, satellitosis,
Cowdry type B intranuclear inclusion bodies in neurons are not a consistent feature of the disease [22], inflammation may persist for several months after necrosis
subsides and is then accompanied by astrocytosis and focal mineralization [35]
• mice, natural infection, subgroup GDVII (SCID-mice): severe degeneration
(often spongiform) and necrosis of neurones and glial cells of the ventral horns (lesser involvement of the dorsal horns of the spinal cord) [29]
• experimental infections in mice (intracerebral inoculation):
• subgroup: DA, BeAn, WW, TO, Yale: acute neuronal degenerative changes and
microglial proliferation primarily in the spinal cord anterior horn, brain stem and
thalamus and perivascular inflammation also in the spinal cord leptomeninges, followed after 1 month p.i. by persistent viral infection of the spinal cord (white matter) with varying degrees of chronic progressive demyelinisation and inflammation
and remyelinisation after a few months (resembles multiple sclerosis in man [31]
[12] [33]); Hydrocephalus and pachymeningitis in mice after inoculation of an DA
virus variant (H101 virus), without viral persistence, no demyelination [36]•subgroup: FA, GDVII: acute polioencephalomyelitis with necrosis of ganglion cells and
neuronophagia of hippocampus, cortex and spinal cord anterior horn and nonsuppurative inflammation, high apoptosis rate in neurons, little if any demyelinisation, no viral persistence in the CNS [37] [38] [39]
Morbidity and mortality
• natural infection: subgroup TO (DA, BeAn 8386, WW, TO, Yale): morbidity low,
little or no mortality (except immunodeficient mice with high morbidity and mortality [29]); strains FA, GDVII: morbidity and mortality high
• experimental infection: (intracerebral inoculation): subgroup TO (DA, BeAn
8386, WW, TO, Yale): morbidity high, mortality low; strains FA, GDVII: morbidity
high (100%), mortality high
Zoonotic potential
• none
Interference with research
• chronic CD4+ response which is initially directed at viral determinants but persists
in the CNS and is directed against multiple myelin autoepitopes; T cell proliferative response in spleen [32]
• increase of CD4+ Th1-cells producing IFN-gamma (DA-strain) [40]
• high m-RNA expression of proinflammatory cytokines in brain and spinal cord of
SJl/J mice beginning at day 5 post infection for tumour necrosis factor-a (TNF-a)
and interferon-g (INF-g); with DA additionally for lymphotoxins LT-a and LT-b, and
with GDVII additionally for interferon-b (IFN- b) and interleukin-6 (IL-6) and high
m-RNA chemokine expression after DA, GDVII and H101-virus infection for Rantes, monocyte chemotactic protein-1 (MCP-1), IP-10 and macrophage inflammatory
proteins (MIP-1b, MIP-1a, MIP-2) [41] [42] [43]
• Increase of INF-a and INF-b in SJL CD4-/- mice (DA-strain) [44]
• Interleukin-1 receptor declines in hippocampus in susceptible strains (SJL/L) [45]
• high apoptosis rate in neurons in GDVII infected mice, in DA infected mice high
apoptosis rate in oligodendrocytes [39]
• inhibition of alpha/beta interferon synthesis in infected L929 cells [46]
• restraint stress has an effect on infected (BeAn strain) animals (increased mortality, increased viral titres, decreased number of lymphocytes) [47]
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to demyelination. Infect Immun, 1975. 11(5): p. 1147-55.
Dal Canto, M.C., et al., Theiler's Murine Encephalomyelitis Virus (TMEV)-Induced
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Martinat, C., et al., The GDVII strain of Theiler's virus spreads via axonal transport. J Virol, 1999. 73(7): p. 6093-8.
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Pathology of Laboratory Animals, ed. U.M. T.C. Jones, R.D.Hunt. 1988: Springer-Verlag.
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small out-of-frame protein in viral persistence and demyelination. Jpn J Infect Dis, 1999.
52(6): p. 228-33.
Tsunoda, I., C.I. Kurtz, and R.S. Fujinami, Apoptosis in acute and chronic central nervous
system disease induced by Theiler's murine encephalomyelitis virus. Virology, 1997.
228(2): p. 388-93.
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7330-4.
Theil, D.J., et al., Alterations in cytokine but not chemokine mRNA expression during
three distinct Theiler's virus infections. J Neuroimmunol, 2000. 104(1): p. 22-30.
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nervous system in the Theiler's virus model of multiple sclerosis. J Neurovirol, 2000. 6
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Author: Bettina Kränzlin, Klinikum Mannheim, Germany
‘Orphan Parvovirus’ ‘OPV’
Mouse Parvovirus (MPV)
Rat Parvovirus (RPV)
History
• serologic evidence for the existence of additional, antigenetically distinct parvoviruses was found during 1983-1984 in mice and rats
• agents were known as 'orphan' parvoviruses or OPV
• mouse and rat orphan parvoviruses have been identified and characterised and
have been renamed mouse parvovirus (MPV) (Ball-Goodrich & Johnson 1994) and
rat parvovirus (RPV) (Ball-Goodrich et al. 1998)
Host species
• natural host: laboratory and wild rats (RPV) and mice (MPV)
Properties of the Virus
• all parvoviruses are highly temperature resistant (Fassolitis et al. 1985)
• all parvoviruses are highly resistant to environmental conditions like e.g. desiccation (Tattersall & Cotmore 1986, Yang et al. 1995, Jacoby et al. 1996)
• MPV is distinct from but related to MVM (Ball-Goodrich & Johnson 1994)
• MPV infection persists after seroconversion even in mice inoculated as adults
(Smith et al. 1993, Jacoby & Ball-Goodrich 1995)
• viral DNA of RPV is detectable in lymphoid tissues for months (Ueno et al. 1997)
Strain susceptibility
• none
Organotropism
• viral replication in mitotically active tissues like, e.g. gastrointestinal tract, lymphocytes, tumours, tropism for lymphoid cells (McKisic et al 1993, Jacoby et al.
1996, Shek et al. 1998)
• predilection for lymphoid tissues of infant and adult mice (MPV) (Jacoby & BallGoodrich 1995) or endothelium and lymphoid tissues of rats (RPV) (Ball-Goodrich
et al. 1998)
• MPV detectable in pancreas, spleen, lymph nodes, lungs, intestines, kidneys (Smith
et al. 1993, Besselsen et al. 1995)
• RPV detectable in lymph nodes, small intestines, kidneys, spleen, etc. (Ueno et al.
1996, Ball-Goodrich et al. 1998)
Clinical disease
• infection asymptomatic even in infant and severely immunocompromised mice
(SCID mice) (Smith et al. 1993, Jacoby et al. 1995) and rats (Jacoby & Ball-Goodrich 1995, Ball-Goodrich et al. 1998)
Pathology
• no pathology or histologic lesions after experimental (i.p., oral) infection (Smith et
al. 1993, Jacoby et al. 1995, Ball-Goodrich et al. 1998)
Morbidity and mortality
• infection asymptomatic even in neonatal and infant mice and rats (Smith et al.
1993, Jacoby & Ball-Goodrich 1995, Ball-Goodrich et al. 1998)
Zoonotic potential
• none
Interference with research
Immunology
• MPV first isolated from a CD8+ T cell clone that had lost function and viability
(McKisic et al. 1993)
• inhibition of proliferation of CD8+ and CD4+T cell clones stimulated with IL-2 or
antigen, but no inhibition of the generation of cytotoxic T cells in mixed lymphocyte
cultures (MLC) (McKisic et al. 1993)
• reduced cytolytic capacity of T cells after MPV infection (McKisic et al. 1996)
• MPV diminishes the of proliferation rate o lymphocytes from spleen and popliteal
lymph nodes, but augments the proliferative response of cells from mesenterial
lymph nodes (McKisic et al. 1996, Jacoby et al. 1996)
• T cell mediated potentiation of rejection of allogeneic skingrafts by MPV infection,
induction of rejection of syngeneic skin grafts (McKisic et al 1998)
• RPV infection may modulate immune function (Ball-Goodrich et al. 1998)
Cell biology
• contaminant of cell lines (McKisic et al. 1993)
• infection transplantable tumours (Ball-Goodrich et al. 1998
Oncology
• MPV accelerates tumour allograft rejection (McKisic et al. 1996)
• contamination of transplantable leukaemia cells by RPV (Ball Goodrich et al. 1998)
• milder disease (reduced hepatosplenomegaly) or delayed onset of clinical signs and
leukaemia in RPV infected tumour-bearing rats compared to uninfected rats (Jacoby et al. 1996, Ball Goodrich et al. 1998)
References
Ball-Goodrich, L. J., and E. Johnson. 1994. Molecular characterization of a newly recognized mouse parvovirus. J. Virol. 68:6476-6486.
Ball-Goodrich, L. J., S. E. Leland, E. A. Johnson, F. X. Paturzo, and R. O. Jacoby. 1998. Rat
parvovirus type 1: the prototype for a new rodent parvovirus serogroup. J. Virol. 72:32893299.
Besselsen, D. G., C. L. Besch-Williford, D. J. Pintel, C. L. Franklin, R. R. Hook, and L. K.
Riley. 1995. Detection of newly recognized rodent parvoviruses by PCR. J. Clin. Microbiol.
33:2859-2863.
Fassolitis, A. C., J. T. Peeler, V. I. Jones, and E. P. Larkin. 1985. Thermal resistance of
three parvoviruses: a possible human isolate, the minute virus of mice, and the latent rat
virus. J. Food. Protect. 48:4-6.
Jacoby, R. O., and L. J. Ball-Goodrich. 1995. Parvovirus infections of mice and rats. Sem.
Virol. 6:329-337.
Jacoby, R. O., E. A. Johnson, L. Ball-Goodrich, A. L. Smith, and M. D. McKisic. 1995. Characterization of mouse parvovirus infection by in situ hybridization. J. Virol. 69:3915-3919.
Jacoby, R. O., L. J. Ball-Goodrich, D. G. Besselsen, M. D. McKisic, L. K. Riley, and A. L.
Smith. 1996. Rodent parvovirus infections. Lab. Anim. Sci. 46:370-380.
McKisic, M. D., D. W. Lancki, G. Otto, P. Padrid, S. Snook, D. C. Cronin, P. D. Lohmar, T.
Wong, and F. W. Fitch. 1993. Identification and propagation of a putative immunosuppressive orphan parvovirus in cloned T cells. J. Immunol. 150:419-428.
McKisic, M. D., F. X. Paturzo, and A. L. Smith. 1996. Mouse parvovirus infection potentiates rejection of tumor allografts and modulates T cell effector function. Transplantation
61:292-299.
McKisic, M. D., J. D. Macy, M. L. Delano, R. O. Jacoby, F. X. Paturzo, and A. L. Smith.
1998. Mouse parvovirus infection potentiates allogeneic skin graft rejection and induces
syngeneic graft rejection. Transplantation 65:1436-1446.
Shek, W. R., F. X. Paturzo, E. A. Johnson, G. M. Hansen, and A. L. Smith. 1998. Characterization of mouse parvovirus infection among BALB/c mice from an enzootically infected
colony. Lab. Anim. Sci. 48:294-297.
Smith, A. L., R. O. Jacoby, E. A. Johnson, F. Paturzo, and P. N. Bhatt. 1993. In vivo studies
with an "orphan" parvovirus of mice. Lab. Anim. Sci. 43:175-182.
Ueno, Y., F. Sugiyama, and K. Yagami. 1996. Detection and in vivo transmission of rat orphan parvovirus (ROPV). Lab. Anim 30:114-119.
Ueno, Y., F. Sugiyama, Y. Sugiyama, K. Ohsawa, H. Sato, and K. Yagami. 1997. Epidemiological characterization of newly recognized rat parvovirus, "rat orphan parvovirus". J.
Vet. Med. Sci. 59:265-269.
Tattersall, P., and S. F. Cotmore. 1986. The rodent parvoviruses, p. 305-348. in: Bhatt, P.
N. et al. (Eds.), Viral and mycoplasmal infections of laboratory rodents. Effects on biomedical research. Academic Press Inc., Orlando, 1986
Yang, F.-C., F. X. Paturzo, and R. O. Jacoby. 1995. Environmental stability and transmission of rat virus. Lab. Anim. Sci. 45:140-144.
Author: Werner Nicklas, DKFZ Heidelberg, Germany
Lymphocytic Choriomeningitis Virus
Host species
• natural host: laboratory and wild mice, pet and laboratory hamsters, wild rats, humans
• guinea pig, rats and baboons can be infected experiementally
• some continius cell lines are virus carrier, e.g. mouse neuroblastoma (N18), baby
hamster kidney cells (BHK-21) and transplantable tumor cells of infected animals
Organotropism
• kidney
• salivary gland
• lymphohemopoietic cells
• other organs
Clinical disease
• clinical signs vary with strain of infected animals, route of inoculation and strain of
virus
• cerebral form in mice follows artificial intracerebral inoculation
• visceral form in mice shows asymptomatic conjunctivitis, ascites, somnolence after
peripheral inoculation
• wasting disease in hamsters (GENOVESI, E.V. 1987)
• febrile illness, grippe-like symptoms in humans (MEATZ, H.M. 1976)
• sensorineural deafness and labyrinth damage, meningeal involvement in humans
(HIRSCH, E. 1976)
• autoimmune haemolytic anaemia in different mice strains (COUTELIER, J.P.
1994)
Pathology
• nonsuppurative leptomeningitis, choroiditis
• inflammatory lesions in many organs
• murine hepatitis (GOSSMANN, J. 1995; LOHLER, J. 1994)
Morbidity and mortality
• LCMV strain ARM ist avirulent for different hamster strains and guinea pig (GENOVESI, E.V. 1987; GENOVESI, E.V. 1989)
• LCMV strain WE causes 100% mortality in guinea pigs (RIVIERE, Y. 1985) and
high morbidity of inbred Syrian golden hamsters
• Prevalence of different hamster inbred strains is known (GENOVESI, E.V. 1987)
Zoonotic potential
• congenital lymphocytic choriomeningitis virus syndrome in humans (EL KARAMANY, R.M. 1991; WRIGHT, R. et al 1997)
• LCMV is the causative agent for hamster associated lymphocytic choriomeningitis
infection of humans (LEHMANN-GRUBE,F. 1979;GARMAN,R.H. 1977;MEATZ,H.M. 1976;ACKERMANN,R.1977)
• Hamster transmit the virus to humans
• Virus is shed in saliva, nasal secretions and urine of infected animals
• wild mice and rats are a natural reservoir of infection (ACKERMANN, R. 1964;
SMITH, A.L. 1993)
Interference with research
Immunology
• LCMV causes a long lasting immunodepression with decrease of proliferation capacity of splenic T-lymphocytes (SARON, M.F. 1991; SARON, M.F. 1990; THOMSON,
A.R. 1982; COLLE, J.H.1993)
• LCMV induces polyclonal cytotoxic T-lymphocyte stimulation (YANG, H.Y. 1989)
• neonatally or congenitally infected mice have a lifelong chronic lymphocytic choriomeningitis virus infection (JAMIESON, B.D. 1987)
• enhances the interleukin 12-mediated immuno toxicities (ORANGE, J.S. 1995;
ORANGE, J.S. 1994)
• LCMV induced different expression of alpha/beta interferons (SANDBERG, K.
1994)
Oncology
• may influence experimental oncology, enhances the fequency of lymphoma after treatment with carcinogen (GARMAN, R.H. 1977)
• enhances the susceptibility for transplantable tumor cell lines (KOHLER, M. 1990)
Physiology
• growth hormon deficiency can occure (OLDSTONE, M.B. 1985)
References
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Ackermann, R., H. Bloedhorn, B. Kupper, I. Winkens and W. Scheide. 1964. Spread of the
lymphocytic choriomeningitis virus among West German mice. I Investigations mostly on
domestic mice (Mus musculus). Zentralbl. Bakteriol. Orig. 194:407-430.
Ackermann, R., S. S. Kalter, R. L. Hebling, B. McCullough, J. Eichberg and A. R. Rodriquez. 1979. Fetal infection of the baboon (Papio cynocephalus) with lymphocytic choriomeningitis virus. Arch. Virol. 60:311-323.
Althage, A., B. Odermatt, D. Moskophidis, T. Kundig, U. Hoffman-Rohrer, H. Hengartner
and R. M. Zinkernagel. 1992. Immunosuppression by lymphocytic choriomeningitits virus
infection: competent effector T and B cells but impaired antigen presentation. Eur. J. Immunol. 22:1803-1812.
Armstrong, D., J. G. Fortner, W. P. Rowe and J. C. Parker. 1969. Meningitis due to lymphocytic choriomeningitis virus endemic in a hamster colony. JAMA 209:265-267.
Blechschmidt, M., W. Gerlich and R. Thomson. 1977. Radioimmunoassay for LCM virus
antigens and anti-LCM virus antibodies and ist application in an epidemiologic survey of
people exposed to syrian hamsters. Med. Microbio. Immunol. Berl. 163:67-76.
Biggar, R. J., J. P. Woodall, P. H. Walter and G. E. Haughie. 1975. Lymphocytic choriomeningitits autbreak associated with pet hamsters. JAMA 232:494-500.
Bowen, G. S., C. H. Calisher, G. W. Winkler, A. L. Kraus, E. H. Fowler, R. H. Garmon, D.
W. Fraser and A. R. Himman. 1975. Laboratory studies of a lymphocytic choriomeningitis
virus outbreak in man and laboratory animals. Am. J. Epidemiol. 102:233-240.
Colle, J. H., M. F. Saron and P. Truffa-Bachi. 1993. Altered cytokine genes expression by
conA-activated spleen cells from mice infected by lymphocytic choriomeningitis virus. Immunol. Lett. 35:247-253.
Coutelier, J. P., S. J. Johnston, M. el-Idrissi and C. J. Pfau. 1994. Involvement of CD4+
cells in lymphocytic choriomeningitis virus-induced autoimmune anaemia and hypergammaglobulinaemia. J. Autoimmun. 5:589-599.
el-Karamany, R. M. and I. Z. Imam. 1991. Antibodies to lymphocytic choriomeningitis virus in wild rodent sera in Egypt. J. Hyg. Epidemio. Microbiol. Immunol. 35:97-103.
Garman, R. H., G. S. Bowen, E. H. Fowler, A. L. Kraus, A. L. Newman, B. R. Rifkin, E. J.
Andrews and W. G. Winkler. 1977. Lymphoma associated with an epizootic of lymphocytic
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Genovesi, E. V., A. J. Johnson and C. J. Peters. 1989. Delayed type-hypersensitivity response of inbred strains of Syrian golden hamsters (Mescricetus auratus) to lethal or nonlethal lymphocytic choriomeningitis virus (LCMV) infections. Microb. Pathog. 8:347-360.
Genovesi, E. V. and C. J. Peters. 1987. Immunosuppression-induced susceptibility of inbred hamsters (Mesocricetus auratus) to lethal disease by lymphocytic choriomeningitis
virus infection. Arch. Virol. 97:71-76.
Genovesi, E. V. and C. J. Peters. 1987. Susceptibility of inbred Syrian golden hamsters
(Mesocricetus auratus) to lethal disease by lymphocytic choriomeningitis virus. Proc. Soc.
Exp. Biol. Med. 185:250-26.
Gossmann, J., J. Lohler, O. Utermohlen and F. Lehmann-Grube. 1995. Murine hepatitis
caused by lymphocytic choriomeningitis virus. II. Cells involved in pathogenesis. Lab. Invest. 72:559-570.
Hirsch, E. 1976. Sensorineural deafness and labyrinth damage due to lymphocytic choriomeningitis. Report of a case. Arch. Otolaryngol. 102:499-500.
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Jamieson, B. D. and R. Ahmed. 1988. T-cell tolerance: exposure to virus in untero does not
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Jamieson, B. D., L. D. Butler and R. Ahmed. 1987. Effective clearance of a persistent viral
infection requires cooperation between virus-specitic Lyt2+ T cells and nonspecific bone
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Jansen. 1972. Golden hamsters, a new infection source of lymphocytic choriomeningitis virus. Hippokrates. 43:369-370.
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Koler, M., B. Ruttner, S. Cooper, H. Hengartner and R. M. Zinkernagel. 1990. Enhanced
tumor susceptibility of immunocompetent mice infected with lymphocytic choriomeningitis
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Maetz, H. M., C. A. Sellers, W. C. Bailey, G. E. Hardy Jr. 1976. Lymphocytic choriomeningitis from pet hamster exposure: a local public health experience. Am. J. Public Health
66:1082-1085.
Nicklas, W., Kraft, V. and B. Meyer. 1993. Contamination of transplantable tumors, cell lines, and monoclonal antibodies wiht rodent viruses. Lab. Anim. Sci. 43:296-300.
Oldstone, M. B., R. Ahmed, M. J. Buchmeier, P. Blount and A. Toshon. 1985. Perturbation
of differentiated functions during viral infection in vivo. I. Relationship of lymphocytic choriomeningitis virus and host strains to growth hormone deficiency. Virology 142:158-174.
Orange, J. S., T.P. Salazar-Mather, S. M. Opal, R. L. Spenser, A. H. Miller, B. S. McEwen
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Pearce, B. D., S. C. Steffensen, A. D. Paoletti, S. J. Hendriksen and M. J. Buchmeier. 1996.
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mapping of lymphocytic choriomeningitis virus pathogenicity: virulence in guenea pigs is
associated with the LRNA segment. J. Virol. 55:704-7049.
Saron, M. F., J. H. Colle, A. Dautry-Varsat and P. Truffa-Bachi. 1991. Activated T lymphocytes from mice infected by lymphocytic choriomeningitis virus display high affinity
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viruses and Mycoplasma pulmonis among wild house mice (Mus demesticus) in southeastern Australia. J. Wildl. Dis. 29:219-229.
Stanwick, T. L. and B. E. Kirk. 1976. Analysis of baby hamster kidney cells persistently infected with lymphocytic choriomeningitis virus. J. Gen. Virol. 32:361-367.
Thomsen, A. R., K. Bro-Jorgensen and B. L. Jensen. 1982. Lymphocytic choriomeningitis
virus-induced immunosuppression: evidence for viral interference with T-cell maturation.
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virus. J. Virol. 48:262-270.
Van-der-Zeijst, B. A., B. E. Noyes, M. E. Mirault, B. Parker, A. D. Osterhaus, E. A. Swyryd,
N. Bleumink, M. C. Horzinek and G. R. Stark. 1983. Persistent infection of some standard
cell lines by lymphocytic choriomeningitis virus: transmission of infection by an intracellular agent. J. Virol. 48:249-261.
Wright, R., D. Johnson, M. Neumann, T. G. Ksiazek, P. Rollin, R. V. Keech, D. J. Bonthius,
P. Hitchon, C. F. Grose, W. F. Bell and J. F. Bale. 1997. Congenital lymphocytic choriomeningitis virus sysdrome: a Disease that minics congenital toxoplasmosis or cytomegalovirus infection. Pediatrics. 100:E91-E96.
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cytotoxic T lymphocyte stimulation. J. Immunol. 142:1710-1718.
Author: Karin Jacobi, Max-Delbrück-Centrum, Berlin, Germany
Mouse Adenoviruses
• mouse adenovirus type 1 (MAd-1) (strain FL)
• mouse adenovirus type 2 (MAd-2) (K87)
Host species
• mouse (positive serologic results in rats are most likely due to a yet unidentified rat
adenovirus (Smith and Barthold, 1987))
Organotropism
• MAd-1: polytropic
• MAd-2: intestine
Clinical disease
• none in naturally infected immunocompetent animals
• wasting disease in athymic mice
Pathology
•MAd-1:
• only experimental infections discribed
• necrotic foci and intranuclear inclusion bodies in various organs (brown fat, myocardium, adrenal glands etc.)
•MAd-2:
• only intestine affected
• intranuclear inclusion bodies in mucosal epithelium little inflammation
Morbidity and mortality
• morbidity: no information, mortality: none in natural infections
• significant strain differences in susceptibility (x6000) (Kring et al., 1995)
Zoonotic potential
• none
Special considerations
• natural occuring MAd-1 has not been reported for many years
• prevalence of MAd-2 is largely unknown in Europe (in Australian wild mice: 37%
(Smith et al., 1993)
• MAd-1 and MAd-2 do not cross-react serologically
Interference with research
Immunology
• transient increase in IL-12 release from macrophages (Coutelier et al., 1995)
Infectiology
• raises susceptibility to E. coli pyelonephritis during persistent infection (Ginder,
1964)
• accelerates experimental scrapie infection (Ehresmann and Hogan, 1986)
Physiology
• induces blood-brain barrier dysfunction (Guida et al., 1995)
References
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Escherichia coli-induced pyelonephritis. J. Exp. Med. 120:1117-1128.
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viruses and Mycoplasma pulmonis among wild house mice (Mus domesticus) in southeastern Australia. J. Wildlife Dis. 29:219-229.
Coutelier, J. P., J. van Broeck and S. F. Wolf. 1995. Interleukin-12 expression after viral infection in the mouse. J. Virol. 69:1955-1958.
Guida, J. D., G. Fejer, L. A. Pirofski, C. F. Brosman and M. S. Horowitz. 1995. Mouse adenovirus type 1 causes a fatal hemorrhagic encephalomyelitis in adult C57BL/6 but not in
BALB/c mice. J. Virol. 69:7674-7681.
Author: F. Homberger
Lactate Dehydrogenase Elevating Virus
Host species
• mouse (Mus musculus, Mus caroli) (Rowsan 1980)
Organotropism
• polytropic strains: liver, spleen, lymphnodes, testistissue
• neurovirulant strain: LDV-C: central nervous system, anterior horn neurons leptominges
• mucosal barrier to viral transmission
Clinical disease
• life long asymptomatic, low level viremic persistence
• immunosuppressed AKR and C58 strain: poliomyelitis with fatal paralysis
• mice are infected by mechanical transfer of tissues or serum from infected animals
• natural transmission between cagemates is rare
Morbidity and mortality
• morbidity and mortality are very low
• morbidity and mortality depend on host strain, immunodeficiency and presence of
murine retro viruses
Zoonotic potencial
• none
Importent notice
• Detection of LDV: measuring LDH levels in mouse plasma PCR-assay ( van der
Logt et al 1994)
Interference with research
Oncology
• enhancement of tumor growth (Mc. Donald 1983, Isakov and Feldmann 1981)
• suppression of chemically induced mouse lung tumorigenesis (Theiss et al 1980)
and foreign body tumorigenesis (Brinton-Darnell-M 1977)
• Contamination of transplantable tumors (Nicklas et al 1993, Isakov et al 1981, Riley et al 1978)
• interactions with oncogene murine retro viruses: ecotropic murine leukemia virus
(Anderson et al 1995, Inada et al 1993, Inada 1993, Inada et Yamazaki 1991, Contag and Plagemann 1989, Contag and Plagemann 1988)
Infectiology
• impaired resistance to bacterial infection (Bonventre et al 1980)
Immunology
• stimulation of B-lymphocyte-activation (Bradley et al 1991, Coutelier et al 1990)
and systemic alteration in lymphocyte circulatory pattern (Mongini 1978)
• elevation of immunoglobulin isotype blood levels IgG2a (Hovinen et al 1990, Li et al
1990, Coutelier et al 1986, Coutelier and Van Snick 1985, Cafruny and Plagemann
1982)
• contaminant of monoclonal antibodies (Nicklas et al 1988)
• induction of interferon production (Lussenhop et al 1982, Nicklas et al 1988, Koi et
al 1981, Evans and Riley 1968, Lagwinska et al 1975)
• influence on immunogenic function of macrophages and macrophage-dependent immunresponse (Isakov at al 1982, Ritzi et al 1982)
• enhancement of natural killer cell activity (Koi et al 1981) and elevation of cytooxic
T-lymphocytes (Even et al 1995)
• reduction of autoantibody production (Verdonck et al 1994, Hayashi et al 1992)
• suppression of cell mediated immunresponses; inhibition of cytokine production IL4, IL-1 (Monteyne et al 1993, Hayashi et al 1991)
Physiology
• changes in hemopoiesis after tumortransplantation (Motycka et al 1981, Viktora et
al 1981)
• suppression of development of glomerulonephritis in autoimmune NZB-mice (Kameyama and Hayashi 1994, Hayashi et al 1993)
• decrease of incidence of diabetes in NOD-mice (Takei et al 1992) and reduction of
streptozotocin-induced diabetis mellitus in CD-1-mice (Hayashi et al 1994)
• changes in clearance capacity for several enzymes and proteins (Winkelhake et al
1978, Hayashi et al 1988, Hayashi et al 1992, Nakayama et al 1990, Brinton et
Plagemann 1983)
• increase of serum lactate dehydrogenase level and other enzymes (Brinton 1982)
• mucosal barrier to LDV transmission exists (Cafruny and Hovinen 1988, Cafruny
et al 1991, Broen et al 1992)
References
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Infection of central nervous system cells by ecotropic murine leukemia virus in C58
and AKR mice and in in utero-infected CE/J mice predisposes mice to paralytic infection by lactate dehydrogenase-elevating virus. J. Virol. 69:308-319.
Bonventre, P. F., H. C. Bubel, J. G. Michael, and A. D. Nickol. 1980. Impaired resistance to bacterial infection after tumor implant is traced to lactic dehydrogenase virus. Infect. Immun. 30:316-319.
Bradley, D. S., J. J. Broen, and W. A. Cafruny. 1991. Infection of SCID mice with lactate dehydrogenase-elevating virus stimulates B-cell activation. Viral Immunol. 4:5970.
Brinton, M. A., M. Darnell, and I. Brand. 1977. Delayed foreign-body tumorigenesis
in mice infected with lactate dehydrogenase-elevating virus: Brief communication. J.
Natl. Cancer Inst. 59:1027-1029.
Brinton, M. A. Lactate dehydrogenase-elevating virus. In „The Mouse in Biomedical
Research (H. L. Foster, J. D. Small, and L. G. Fox, eds.), Vol. 2, p.194. Academic Press
1982; New York.
Brinton, M. A., P. G. Plagemann. 1983. Clearance of lactate dehydrogenase by SJL/J
mice infected with lactate dehydrogenase-elevating virus. J. Reticuloendothel Soc.
33:391-400.
Broen, J. J., S. E. DesJarlais, R. G. Duman, S. N. Anderson, R. A. Mueller, W. A.
Cafruny. 1992. Virucidal effect of murine duodenal extracts: studies with lactate dehydrogenase-elevating virus. Antiviral Res. 18:327-340.
Cafruny, W. A., and P. G. Plagemann. 1982. Immune response to lactate dehydrogenase-elevating virus: isolation of infectious virus-immunoglobulin G complexes and
quantitation of specific antiviral immuno-globulin G response in wild-type and nude
mice. Infect. Immun. 37:1001-1006.
Cafruny, W. A., D. E. Hovinen. 1988. The relationship between route of infection and
minimum infectious dose: studies with lactate dehydrogenase-elevating virus. J. Virol. Methods. 20:265-268.
Cafruny, W. A. 1989. Lactate dehydrogenase-elevating virus: biology and pathogenesis. Crit. Rev. Microbiol. 17:107-119.
Cafruny, W. A., S. E. DesJarlais, M. L. Hecht, J. J. Broen, and R. A. Jaqua. 1991. Enhancement of murine susceptibility to oral lactate dehydrogenase-elevating virus infection by non-steroidal anti-inflammatory agents, and antagonism by misoprostol.
Antiviral Res. 15:77-83.
Contag, C. H., and P. G. Plagemann. 1988. Susceptibility of C58 mice to paralytic disease induced by lactate dehydrogenase-elevating virus correlates with increased expression of endogenous retrovirus in motor neurons. Microb. Pathog. 5:287-296.
Contag, C. H., and P. G. Plagemann. 1989. Age-dependent poliomyelitis of mice: expression of endogenous retrovirus correlates with cytocidal replication of lactate dehydrogenase-elevating virus in motor neurons. J. Virol. 63:4362-4369.
Coutelier, J. P., and J. Van-Snick. 1985. Isotypically restricted activation of B lymphocytes by lactic dehydrogenase virus. Eur. J. Immunol. 15:250-255.
Coutelier, J. P., E. Van-Roost, P. Lambotte, and J. Van-Snick. 1986. The murine antibody response to lactate dehydrogenase-elevating virus. J. Gen. Virol. 67:1099-1108.
Coutelier, J. P., P.G. Coulie, P. Wauters, H. Heremans, and J. T. van-der-Logt. 1990.
In vivo polyclonal B-lymphocyte activation elicited by murine viruses. J. Virol.
64:5383-5388.
Evans, R., and V. Riley. 1968. Circulating interferon in mice infected with the lactate
dehydrogenase-elevating virus. J. Gen. Virol. 3:449-452.
Even, C., R. R. Rowland, and P. G. Plagemann. 1995. Cytotoxic T cells are elicited during acute infection of mice with lactate dehydrogenase-elevating virus but disappear
during the chronic phase of infection. J. Virol. 69:5666-5676.
Hayashi, T., K. Salata, A. Kingman, A.L. Notkins. 1988. Regulation of enzyme levels
in the blood. Influence of environmental and genetic factors on enzyme clearance.
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Hayashi, T., H. Iwata, T. Hasegawa, M. Ozaki, H. Yamamoto, and T. Onodera. 1991.
Decrease in neutrophil migration induced by endotoxin and suppression of interleukin-1 production by macrophages in lactic dehydrogenase virus-infected mice. J.
Comp. Pathol. 104:161-170.
Hayashi, T., M. Ozaki, I. Mori, M. Saito, T. Itoh, and H. Yamamoto. 1992. Enhanced
clearance of lactic dehydrogenase-5 in severe combined immunodeficiency (SCID)
mice: effect of lactic dehydrogenase virus on enzyme clearance. Int. J. Exp. Pathol.
73:173-181.
Hayashi, T. 1992. Effect of prostaglandin E2 on plasma lactic dehydrogenase activity
in (NZB x NZW)F1 mice with a chronic infection of lactic dehydrogenase virus. J.
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Hayashi, T., I. Mori, and H. Yamamoto. 1992. Lactic dehydrogenase virus infection
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Hayashi, T., Y. Noguchi, and Y. Kameyama. 1993. Suppression of development of antinuclear antibody and glomerulonephritis in NZB x NZWF1 mice by persistent infection with lactic dehydrogenase virus: possible involvement of superoxide as a progressive effector. Int. J. Exp. Pathol. 74:553-560.
Hayashi, T., S. Hashimoto, and Y. Kameyama. 1994. Reduced streptozotocin-induced
insulitis in CD-1 mice by treatment with anti-intercellular adhesion molecule-1 and
anti-lymphocyte function associated antigen-1 monoclonal antibodies together with
lactic dehydrogenase virus infection. Int. J. Exp. Pathol. 75:117-121.
Hayashi, T., S. Hashimoto, and A. Kawashima. 1994. Effect of infection by lactic dehydrogenase virus on expression of intercellular adhesion molecule-1 on vascular endothelial cells of pancreatic islets in streptozotocin-induced insulitis of CD-1 mice.
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Hovinen, D. E., D. S. Bradley, and W. A. Cafruny. 1990. Analysis of immunoglobulin
isotype blood levels, splenic B-cell phenotypes, and spleen cell immunoglobulin gene
expression in mice infected with lactate dehydrogenase-elevating virus. Viral. Immunol. 3:27-40.
Inada, T. 1993. Replication of lactate dehydrogenase-elevating virus in various species cell lines infected with dual-, ampho- and xenotropic murine leukaemia viruses
in vitro. Virus Res. 27:267-281.
Inada, T., H. Kikuchi, and S. Yamazaki. 1993. Comparison of the ability of lactate dehydrogenase-elevating virus and its virion RNA to infect murine leukemia virus-infected or -uninfected cell lines. J. Virol. 67:5698-5703.
Isakov, N., M. Feldman, and S. Segal. 1981. Effect of lactic dehydrogenase virus infection on tumor induction and tumor growth. Cancer Res. 41:667-672.
Isakov, N., S. Segal, and M. Feldman. 1981. The immunoregulatory characteristics of
the lactic dehydrogenase virus (LDV), a common contaminant of tumors. Cell. Mol.
Biol. 27:83-96.
Isakov, N., M. Feldman, and S. Segal. 1982. Lactic dehydrogenase virus (LDV) impairs the antigen-presenting capacity of macrophages yet fails to affect their phagocytic activity. Immunobiology 162:15-27.
Kameyama, Y., and T. Hayashi. 1994. Suppression of development of glomerulonephritis in NZB x NZWF1 mice by persistent infection with lactic dehydrogenase virus: relations between intercellular adhesion molecule-1 expression on endothelial
cells and leucocyte accumulation in glomeruli. Int. J. Exp. Pathol. 75:295-304.
Koi, M., M. Saito, T. Ebina, and N. Ishida. 1981. Lactate dehydrogenase-elevating
agent is responsible for interferon induction and enhancement of natural killer cell
activity by inoculation of Ehrlich ascites carcinoma cells into mice. Microbiol. Immunol. 25:565-574.
Lagwinska, E., C. C. Stewart, C. Adles, and S. Schlesinger. 1975. Replication of lactic
dehydrogenase virus and Sindbis virus in mouse peritoneal macrophages. Induction
of interferon and phenotypic mixing. Virology 65:204-214
Li, X., B. Hu, J. Harty, C. Even, and P. G. Plagemann. 1990. Polyclonal B cell activation of IgG2a and IgG2b production by infection of mice with lactate dehydrogenaseelevating virus is partly dependent on CD4+ lymphocytes. Viral Immunol. 3:273-288.
Lussenhop, N., B. Holmes, W. A. Cafruny, and P. G. Plagemann. 1982. Acute infection
of mice with lactate dehydrogenase-elevating virus enhances Fc and complement receptor activity of peritoneal macrophages. J. Gen. Virol. 61:25-32.
McDonald, T. L. 1983. Blocking of cell-mediated immunity to Moloney murine sarcoma virus-transformed cells by lactate dehydrogenase virus-antibody complex. J. Natl.
Cancer Inst. 70:493-497.
Mongini, P. K., and L. T. Rosenberg. 1978. Lactic dehydrogenase virus alteration of
lymphocyte circulation. J. Immunol. 120:459-462.
Motycka, K., A. Balcarova, A. Pezlarova, and A. Jandova. 1981. Changes in hemopoiesis of mice of the C3H strain following transplantation of Gardner lymphosarcoma
and infection with LDH-virus. III. Blood proteins. Neoplasma 28:95-102.
Monteyne, P., J. Van-Broeck, J. Van-Snick, and J. P. Coutelier. 1993. Inhibition by lactate dehydrogenase-elevating virus of in vivo interleukin 4 production during immunization with keyhole limpet haemocyanin. Cytokine 5:394-397.
Nakayama, H., T. Hayashi, K. F. Salata, and A. L. Notkins. 1990. Flow cytometry to
identify cell types to which enzymes bind. Effect of lactic dehydrogenase virus on enzyme binding. J. Biol. Chem. 265:14355-14357.
Nicklas, W., M. Giese, R. Zawatzky, H. Kirchner, and P. Eaton. 1988. Contamination
of a monoclonal antibody with LDH-virus causes interferon induction. Lab. Anim. Sci.
38:152-154.
Nicklas, W., V. Kraft, and B. Meyer. 1993. Contamination of transplantable tumors,
cell lines, and monaclonal antibodies with rodent virus. Lab. Anim. Sci. 43:296-300.
Riley, V., D. H. Spackman, G. A. Santisteban, G. Dalldorf, I. Hellstrom, K. E. Hellstrom, E. M. Lance, K. E. Rowson, B. W. Mahy, P. Alexander, C. C. Stock, H. O. Sjogren, V. P. Hollander, and M. C. Horzinek. 1978. The LDH virus: an interfering biological contaminant. Science 200:124-126.
Ritzi, D. M., M. Holth, M. S. Smith, W. J. Swart, W. A. Cafruny, G. W. Plagemann,
and J. A. Stueckemann. 1982. Replication of lactate dehydrogenase-elevating virus in
macrophages. 1. Evidence for cytocidal replication. J. Gen. Virol. 59:245-262.
Rowson, K. E. 1980. A new host species for lactic dehydrogenase virus. Experientia
36:1066-1067.
Takei, I., Y. Asaba, T. Kasatani, T. Maruyama, K. Watanabe, T. Yanagawa, T. Saruta,
and T. Ishii. 1992. Suppression of development of diabetes in NOD mice by lactate dehydrogenase virus infection. J. Autoimmun. 5:665-673
Theiss, J. C., M. B. Shimkin, G. D. Stoner, A. J. Kniazeff, and R. D. Hoppenstand.
1980. Effect of lactate dehydrogenase virus on chemically induced mouse lung tumorigenesis. Cancer Res. 40:64-66.
van der Logt, J. T., J. Kissing, and W. J. Melchers. 1994. Enzymatic amplification of
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Viktoria, L., K. Motycka, A. Jirasek, A. Balcarova, and K. Neuwirtova. 1981. Changes
in hemopoiesis of mice of the C3H strain following transplantation of Gardner
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Winkelhake, J. L., B. M. Elcombe, and R.J. Chang. 1978. Protracted circulating lifetimes of mannose-terminated glycoproteins and aggregated albumin in mice infected
with LDH-elevating virus. Physiol. Chem. Phys. 10:305-322.
Toolan’s H-1 Virus (H-1)
Host species
• natural host: laboratory and wild rats (JACOBY et al. 1979)
• hamsters and other species can be infected experimentally (KILHAM & MARGOLIS 1975, National Research Council 1991)
• mouse cells cannot be infected by H-1 (TATTERSALL & COTMORE 1986)
Properties of the virus
• highly temperature resistant (FASSOLITIS et al. 1985)
• highly resistant at different pH values, desiccation and other environmental conditions (GREENE 1963, TATTERSALL & COTMORE 1986)
Strain susceptibility
• none
Organotropism
• viral replication only in mitotically active tissues like, e.g. embryo, intestines, tumours (JACOBY et al. 1979)
• pathogenic for the developing liver and cerebellum (JACOBY & BALL-GOODRICH
1995)
Clinical disease
• no clinical signs after natural infection (National Research Council 1991)
• fetal and neonatal abnormalities (KILHAM & MARGOLIS 1975)
• cerebellar hypoplasia and chronic ataxia in young animals after experimental infection (MARGOLIS & KILHAM 1975)
Pathology
• no lesions after natural infection
• experimental malformations of the central nervous system, skeleton, and teeth
(KILHAM & MARGOLIS 1975)
• hepatocellular necrosis after partial hepatectomy (RUFFOLO et al. 1966)
Morbidity and mortality
• no clinical signs after natural infection
• mongoloid-like deformations in hamsters experimentally infected as newborns
(TOOLAN & LEDINKO 1968)
Zoonotic potential
• none
Interference with research
Physiology
• delayed healing of bone fractures and altered callus formation (KILHAM & MARGOLIS 1975)
• inhibition of lipid formation in rat kidney cells in vitro (SCHUSTER et al. 1991)
• increased abortion rate (KILHAM & MARGOLIS 1969)
Pathology
• hepatocellular necrosis after partial hepatectomy (RUFFOLO et al. 1966)
Infectiology
• viral inclusion bodies in animals bearing larval forms of tapeworms (KILHAM et al.
1970)
Cell biology
• contaminant of permanent human cell lines (HALLAUER et al. 1971)
• infection of human cells is increased after oncogenic transformation (TOOLAN &
LEDINKO 1965, DUPRESSOIR et al. 1989, CHEN et al. 1986, ROMMELAERE &
CORNELIS 1991)
• human cells naturally or experimentally transformed with DNA tumour viruses are
permissive for H-1 infection (FAISST et al. 1989)
• in various human lymphoma-derived cells a persistent infection can occur (FAISST
et al. 1990)
Teratology
• fetal deaths and congenital malformation after inoculation into pregnant hamsters
(FERM & KILHAM 1964)
Infectiology
• H-1 together with KRV and C. piliforme can influence the prevalence rate of Yersinia-induced arthritis in rats (GRIPENBERG-LERCHE & TOIVANEN 1993, 1994)
Oncology
• greater susceptibility of human oncogenic transformed cells and tumour-derived
cell lines than normal untransformed parental cells (CORNELIS et al. 1988, ROMMELAERE & CORNELIS 1991)
• presence of H-1 virus reduces the number of tumours produced by an oncogenic
adenovirus in hamsters (TOOLAN & LEDINKO 1968)
• reduced incidence of spontaneous tumours in hamsters experimentally infected at
birth (TOOLAN 1967, TOOLAN et al. 1982)
• reduced incidence of chemically induced tumours in experimentally infected hamsters (TOOLAN et al. 1982)
• inhibition of tumour formation in nude mice from a transplanted human tumour
and retardation of tumour growth (DUPRESSOIR et al. 1989)
References
Chen, Y. Q., F. de Foresta, J. Hertoghs, B. L. Avalosse, J. J. Cornelis, and J. Rommelaere. 1986. Selective killing of simian virus 40-transformed human fibroblasts by
parvovirus H-1. Cancer Res. 46:3574-3579.
Cornelis, J. J., P. Becquart, N. Duponchel, N. Salome, B. L. Avalosse, M. Namba, and
J. Rommelaere. 1988. Transformation of human fibroblasts by ionizing radiation, a
chemical carcinogen, or simian virus 40 correlates with an increase in susceptibility
to the autonomous parvoviruses H-1 virus and minute virus of mice. J. Virol.
62:1679-1686.
Dupressoir, T., J. M. Vanacker, J. J. Cornelis, N. Duponchel, and J. Rommelaere.
1989. Inhibition by parvovirus H-1 of the formation of tumors in nude mice and colonies in vitro by transformed human mammary epithelial cells. Cancer Res. 49:32033208.
Faisst, S., J. R. Schlehofer, and H. zur Hausen. 1989. Transformation of human cells
by oncogenic viruses supports permissiveness for parvovirus H-1 propagation. J. Virol. 63:2152-2158.
Faisst, S., S. Bartnitzke, J. R. Schlehofer, and H. zur Hausen. 1990. Persistence of
parvovirus H-1 DNA in human B- and T-lymphoma cells. Virus Res. 16:211-224.
Fassolitis, A. C., et al. 1985. Thermal resistance of three parvoviruses: a possible human isolate, the minute virus of mice, and the latent rat virus. J. Food. Protect. 48:46.
Ferm, V. H., and L. Kilham. 1964. Congenital anomalies induced in hamster embryos
with H-1 virus. Science 145:510-511.
Greene, E. L. 1963. Physical and chemical properties of H-1 virus. pH and heat stability of the hemagglutinating property. Proc. Soc. Exp. Biol. Med. 118:973-975.
Gripenberg-Lerche, C., and P. Toivanen. 1993. Yersinia associated arthritis in SHR
rats: effect of the microbial status of the host. Ann. Rheum. Dis. 52:223-228.
Gripenberg-Lerche, C., and P. Toivanen. 1994. Variability in the induction of experimental arthritis: Yersinia associated arthritis in Lewis rats. Scand. J. Rheumatol.
23:124-127.
Hallauer, C., G. Kronauer, and G. Siegl. 1971. Parvoviruses as contaminants of permanent human cell lines. I. Virus isolations from 1960 to 1970. Arch. Ges. Virusforsch. 35:80-90.
Jacoby, R. O., P. N. Bhatt, and A. M. Jonas. 1979. Viral Diseases, in: H. J. Baker, J. R.
Lindsey & S. H. Weisbroth (Eds.): The laboratory rat, Vol. 1, Biology and Diseases,
Academic Press, New York, 1979.
Jacoby, R. O., and L. Ball-Goodrich. 1995. Parvovirus infections of mice and rats.
Sem. Virol. 6:329-337.
Kilham, L., and G. Margolis. 1969 Transplacental infection of rats and hamsters induced by oral and parenteral inoculations of H1 and rat viruses (RV). Teratology
2:111-223.
Kilham. L., G. Margolis, and E. D. Colby. 1970. Enhanced proliferation of H-1 virus
in livers of rats infected with Cysticercus fasciolaris. J. Infect Dis. 121:648-652.
Kilham. L., and G. Margolis. 1975. Problems of human concern arising from animal
models of intrauterine and neonatal infections due to viruses: a review. I. Introduction and virologic studies. Progr. Med. Virol. 20:113-143.
Margolis, G., and L. Kilham. 1975. Problems of human concern arising from animal
models of intrauterine and neonatal infections due to viruses: a review. II. Pathologic
studies. Progr. Med. Virol. 20:144-179.
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Rommelaere; J., and J. J Cornelis. 1991. Antineoplastic activity of parvoviruses. J.
Virol. Methods 33:233-251.
Ruffolo, P. R., G. Margolis, and L. Kilham. 1966. The induction of hepatitis by prior
partial hepatectomy in resistant adult rats infected with H-1 virus. Am J. Pathol.
49:795-824.
Schuster, G. S., G. B. Caugham, and N. L. O’Dell. 1991. Altered lipid metabolism in
parvovirus-infected cells Microbios. 66:134-155.
Tattersall, P., and S. F. Cotmore. 1986. The rodent parvoviruses, in: Bhatt, P. N. et al.
(Eds.), Viral and mycoplasmal infections of laboratory rodents. Effects on biomedical
research. Academic Press Inc., Orlando, 1986.
Toolan, H. W. 1967 Lack of oncogenic effect of the H-viruses for hamsters. Nature
214:1036.
Toolan, H. W., and N. Ledinko. 1965. Growth and cytopathogenicity of H-1 viruses in
human and simian cell cultures. Nature 214:812-813.
Toolan, H. W., and N. Ledinko. 1968. Inhibition by H-1 virus of the incidence of tumors produced by adenovirus 12 in hamsters. Virology 35:475-478.
Toolan, H. W., S. L. Rhode, and J. F. Gierthy. 1982. Inhibition of 7, 12-Dimethylbenz(a)anthracene-induced tumors in syrian hamsters by prior infection with H-1
parvoviruses. Cancer Res. 42:2552-2555.
Author: Werner Nicklas, DKFZ Heidelberg, Germany
Kilham Rat Virus (KRV)
Host species
• natural host: laboratory and wild rats,
• hamsters and other species such as Mastomys natalensis can be infected experimentally (KILHAM 1961, RABSON et al. 1961, National Research Council 1991)
Properties of the virus
• highly temperature resistant (FASSOLITIS et al. 1985)
• highly resistant to environmental conditions like e.g. desiccation (LUM & SCHREINER 1963, TATTERSALL & COTMORE 1986, YANG et al. 1995)
• evidence for virus persistence in rats after natural infection (ROBEY et al. 1968,
LIPTON et al. 1973)
• persistent infection after experimental infection of infant and juvenile rats (PATURZO et al. 1987, JACOBY et al. 1991)
• persistent infection in T cell-deficient rats (GAERTNER et al. 1995)
• limited infection in euthymic rats
Strain susceptibility
• none (JACOBY & BALL-GOODRICH 1995)
Organotropism
• viral replication only in mitotically active tissues (TENNANT & HAND 1970) like,
e.g. embryo, intestines, tumours
• predilection for the developing liver and cerebellum (KILHAM & MARGOLIS 1966,
COLE et al. 1970)
Clinical disease
• infection often asymptomatic (LUM 1970, ROBINSON et al. 1971), but can be severe or lethal, especially in athymic infant rats (GAERTNER et al. 1991)
• cases of spontaneous clinical disease with deaths have been reported (KILHAM &
MARGOLIS 1966, COLEMAN et al. 1983)
• fetal and neonatal abnormalities (KILHAM & MARGOLIS 1975)
• cerebellar hypoplasia and ataxia in hamsters after experimental infection (KILHAM & MARGOLIS 1964)
• periodontal disease in hamsters (National Research Council 1991)
Pathology
• haemorrhage and infarction especially in the central nervous system (EL DADAH
et al. 1967, COLE et al. 1970, MARGOLIS & KILHAM 1970, BARINGER &
NATHANSON 1972)
• intranuclear parvoviral inclusions in areas of necrosis among clinically affected
rats (JACOBY et al. 1979, LUSSIER 1991)
• mongoloid-type deformity in new-born hamsters after experimental infection
(BAER & KILHAM 1962)
• cerebellar lesions in cats after experimental infection (KILHAM & MARGOLIS
1965)
Morbidity and mortality
• pathogenic in fetal and infant rats (JACOBY & BALL-GOODRICH 1995)
• acute disease in hamsters after experimental infection (KILHAM 1961)
• prenatal infections in rats (JACOBY et al. 1988)
Zoonotic potential
• none
Interference with research
Pathology
• increased leukocyte adhesion in the aortic epithelium (GABALDON et al. 1992)
• hamsters surviving experimental infection develop stunted growth resembling
mongolism (KILHAM 1961)
Immunology
• infection of T and B lymphocytes and suppression of various lymphocyte functions
(MCKISIC et al. 1995)
• stimulates autoreactive T lymphocytes specific for pancreatic antigens (BROWN et
al. 1993)
• virus alters susceptibility to autoimmune diabetes in a rat strain which is normally
resistant to this syndrome (GUBERSKI et al. 1991, STUBBS et al. 1994, ELLERMANN et al. 1996)
• alters cytotoxic lymphocyte activity (DARRIGRAND et al. 1984)
• depresses lymphocyte viability and a variety of T cell functions like, e.g. in vitro
lymphoproliferative responses (CAMPBELL et al. 1977 a, b)
• stimulates interferon production (KILHAM et al. 1968)
Physiology
• inhibition of lipid formation in rat kidney cells in vitro (SCHUSTER et al. 1991)
• increased abortion rate (KILHAM & MARGOLIS 1969)
Cell biology
• contaminant of cell lines (HALLAUER et al. 1971)
• persistent infection of cell lines and transplantable tumours (WOZNIAK & HETRICK 1969, BASS & HETRICK 1978, National Research Council 1991)
• Teratology
• congenital malformation (MARGOLIS & KILHAM 1975)
• death and resorption of foetuses (KILHAM & MARGOLIS 1966)
Infectiology
• necrosis in the lung may support secondary colonisation with other microorganisms
such as Pasteurella pneumotropica (CARTHEW & GANNON 1981)
• KRV together with H-1 and C. piliforme can influence the prevalence rate of Yersinia-induced arthritis in rats (GRIPENBERG-LERCHE & TOIVANEN 1993, 1994)
Oncology
• contamination of transplantable or chemically induced tumours (KIILHAM & OLIVIER 1959, CAMPBELL et al. 1977, NICKLAS et al. 1993)
• contamination of leukaemias or leukaemia virus preparations (KILHAM & MOLONEY 1964, BERGS 1967, SPENCER 1967)
• suppression of leukaemia induction by Moloney virus (BERGS 1969)
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Campbell, D. A., Jr., E. K. Manders, J. R. Oehler, G. D. Bonnard, R. K. Oldham, and
R. B. Herberman. 1977a. Inhibition of in vitro lymphoproliferative responses by in
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Gabaldon, M., C. Capdevila, and A. Zuniga. 1992. Effect of spontaneous pathology
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Gaertner, D. J., R. O. Jacoby, F. X. Paturzo, E. A. Johnson, J. L. Brandsma, and A. L.
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Persistent rat virus infection in juvenile athymic rats and its modulation by antiserum. Lab. Anim. Sci. 45:249-253.
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Kilham, L., and G. Margolis. 1964. Cerebellar ataxia in hamsters inoculated with rat
virus. Science 143:1047-1048 .
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virus in tissues of inoculated rats. J. Natl. Cancer Inst. 32:523-531.
Kilham, L., C. E. Buckler, V. H. Ferm, and S. Baron. 1968. Production of interferon
during rat virus infection. Proc. Soc. Exp. Biol. Med. 129:274-278.
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Lussier, G (Ed.). 1991 Detection methods for the identification of rodent viral and
mycoplasmal infections. Lab. Anim. Sci. 41:199-225.
Lum, G. S. 1970. Serological studies of rat virus in relation to tumors. Oncology
24:335-343.
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Margolis, G., and L. Kilham. 1970. Parvovirus infections, vascular endothelium and
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Nicklas, W., V. Kraft, and B. Meyer. 1993. Contamination of transplantable tumors,
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Paturzo, F. X., R. O. Jacoby, P. N. Bhatt, A. L. Smith, D. J. Gaertner, and R. B. Ardito.
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Arch. Virol. 95:137-142.
Rabson, A. S., L. Kilham, and R. L. Kirschstein. 1961 Intranuclear inclusions in Rattus (Mastomys) natalensis infected with rat virus. J. Natl. Cancer Inst. 27:1217-1223.
Robey, R. E., D. R. Woodman, and F. M. Hetrick. 1968. Studies on the natural infection of rats with the Kilham rat virus. Am. J. Epidemiol. 88:139-143.
Robinson, G. W., N. Nathanson, and J. Hodous. 1971. Sero-epidemiological study of
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Schuster, G. S., G. B. Caughman, and N. L. O’Dell. 1991. Altered lipid metabolism in
parvovirus-infected cells. Microbios 66:134-155.
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with Kilham rat virus. J. Virol. 4:313-314.
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Tennant, R. W., and R. E. Hand. 1970. Requirement of cellular synthesis for Kilham
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Author: Werner Nicklas, DKFZ Heidelberg, Germany
Guinea Pig Adenovirus (GPAdV)
Host species
• guinea pig
Organotropism
• lungs, upper respiratory tract
Clinical disease
• dyspnea (rapid, shallow, labored or noisy breathing), a hunched posture, piloerection (roughened coat), eventually sensitivity to touch, hypothermia and death in
sporadic cases within 1 hour or 1 day caused by an acute lobar bronchopneumonia
(necrotizing bronchiolitis)
Morbidity and mortality
• Note: The virus alone seems not to be able to elicit the disease; some additional weakening factors are necessary (multi-factorial disease). Nothing is known about the
prevalence of the virus in infected colonies. Morbidity is considered to be low and
mortality close to 100% (no animal showing clinical dyspnea recovered). Subclinical
infection of the upper respiratory tract has recently been found.
Interference with research
• Sudden death of experimental guinea pigs in sporadic cases (or reaching about 5 %
mortality of a batch at the most). No other interference is known.
Note
• Diagnostic method: beside histology and electron microscopy also PCR (Pring-Akerblom et al., 1997). May be used to detect subclinical infection in the upper resiratory tract (Butz and Homberger, 1997).
References
Brandon, D. R. 1995. Adenovirus: an "in-house" investigation into the cause of lethal
pneumonia in guinea pigs. Anim. Technol. 46:139-151.
Brennecke, L. H., T. M. Dreier, and W. S. Strokes. 1983. Naturally occurring virus associated respiratory disease in two guinea pigs. Vet. Pathol. 20:488-491.
Butz, N., and F. R. Homberger. 1997. Pathogenesis of the adenovirus infection in the
guinea pig. GV-SOLAS meeting, 9.-11. Sept., Jena, Germany.
Feldmann, S. H., J. A. Richardson, and F. J. Clubb. 1990. Necrotizing viral bronchopneumonia in guinea pigs. Lab. Anim. Sci. 40:82-83.
Hsiung, G. D., B. P. Griffith, and F. J. Bia. 1986. Herpesviruses and retroviruses of
guinea pigs, p. 451-504, In Bhatt, P.N., R.O. Jacoby, H.C.III. Morse, A.E. New (eds.),
Viral and mycoplasmial infections of laboratory rodents. Effects on biomedical research. Academic Press Inc., Orlando, Florida.
Junker, U., and G. E. Bestetti. 1988. Adenoviruspneumonie beim Meerschweinchen.
Schw. Arch. Tierheilk 130:629-633.
Kaup, F. J., S. Naumann, I. Kunstyr, and W. Drommer. 1984. Experimental viral
pneumonia in guinea pigs. An ultrastructural study. Vet. Pathol. 21:521-527.
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Kunstyr, I., J. Maess, S. Naumann, F. J. Kaup, and K .W. Knocke. 1984. Adenoviruspneumonia in guinea pigs: An experimental reproduction of the disease. Lab.
Anim. 18:55-60.
Naumann, S., I. Kunstyr, I. Langer, J. Maess, and R. Hörning. 1981. Lethal pneumonia in guinea pigs associated with a virus. Lab. Anim. 15:235-242.
Pring-Akerblom, P., K. Blazek, J. Schramlova, and I. Kunstyr. 1997. PCR for diagnosis of adenovirus associated pneumonia in guinea pigs. J. Vet. Diagn. Invest. 9:232236.
Author: I. Kunstyr
Pneumonia Virus of Mice
Host species
• mouse, rat, hamster, guinea pig, (rabbit)
Organotropism
• respiratory tract
Clinical disease
• asymptomatic in euthymic animals (Smith, et al., 1984)
• chronic pneumonia and death in athymic (nude) mice (Richter, et al., 1988) (Weir, et
al., 1988)
Pathology
• mild necrotizing rhinitis, necrotizing bronchiolitis and nonsuppurative interstitial
pneumonia
Morbidity and mortality
• morbidity: from 20% (in mice) to 50% (in rats and hamsters)
• mortality: none, except in immunodefecient mice
Interference with research
Physiology
• increases the suseptibility to diabetes induction by streptozotocin in BALB/cByJ
males mice (Leiter, et al., 1988)
• causes significant decreases in body weights of F344/NCr rats but not of B6C3F1
mice (Rao, et al., 1989a+b)
Pathology
• produces an interstitial pneumonia with virus demonstrated in the bronchial epithelium but also in the alveolar walls and alveolar macrophages in germ-free athymic and euthymic mice (Carthew and Sparrow, 1980a+b)
• causes hydrocephalus after intracerebral inoculation of neonatal mice (Lagace-Simard, et al., 1980)
Oncology
• lowers the prevalence of leukemia in male F344/NCr rats (Rao, et al., 1989)
References
Carthew, P., and S. Sparrow. 1980a. A comparison in germ-free mice of the pathogenesis of Sendai virus and mouse pneumonia virus infections. J. Pathol. 130:153-158.
Carthew, P., and S. Sparrow. 1980b. Persistence of pneumonia virus of mice and Sendai virus in germ-free (nu/nu) mice. Br. J. Exp. Pathol. 61:172-175.
Lagace-Simard, J., J. P. Descoteaux, and G. Lussier. 1980. Experimental pneumovirus infections: 1. Hydrocephalus of mice due to infection with pneumonia virus of
mice (PVM). Am. J. Pathol. 101:31-40.
Leiter, E. H., P. H. Le, M. Prochazka, S. M. Worthen, and K. Huppi. 1988. Genetic
and environmental control of diabetes induction by multi-dose streptozotocin in two
BALB/c substrains. Diab. Res. 9:5-10.
Rao, G. N., J. K. Haseman, and J. Edmondson. 1989a. Influence of viral infections on
body weight, survival, and tumor prevalence in Fischer 344/NCr rats on two-year studies. Lab. Anim. Sci. 39:389-393.
Rao, G. N., W. W. Piegorsch, D. D. Crawford, J. Edmondson, and J. K. Haseman.
1989b. Influence of viral infections on body weight, survival, and tumor prevalence of
B6C3F1 (C57BL/6N x C3H/HeN) mice in carcinogenicity studies. Fund. Appl. Toxicol.
13:156-164.
Richter, C. B., J. E. Thigpen, C. S. Richter, and J. M. Mackenzie, Jr. 1988. Fatal
pneumonia with terminal emaciation in nude mice caused by pneumonia virus of
mice. Lab. Anim. Sci. 38:255-261.
Smith, A. L., V. A. Carrano, and D. G. Brownstein. 1984. Response of weanling random-bred mice to infection with pneumonia virus of mice (PVM). Lab. Anim. Sci.
34:35-37.
Weir, E. C., D. G. Brownstein, A. L. Smith, and E. A. Johnson. 1988. Respiratory disease and wasting in athymic mice infected with pneumonia virus of mice. Lab.
Anim. Sci. 38:133-137.
Author: F. Homberger
Sialodacryoadenitis Virus,
Rat Corona Virus
Host species
• rat
Organotropism
• salivary and lacrimal (incl. Harderian) glands, respiratory tract
Clinical disease
• enzootic: asymptomatic or mild conjunctivitis in suckling rats
• epizootic: nasal and ocular discharge, porphyrin staining, corneal ulceration, swelling of the neck, exophthalmus
• SDAV may persisted for at least 6 months in athymic rats (Hajjar et al., 1991; Weir
et al., 1990)
Pathology
• acute: coagulation necrosis of the ductual structure of the salivary and lacrimal
glands
• reparative phase: squamous metaplasia of ductual and acinar structures of the salivary and lacrimal glands
Morbidity and mortality
• morbidity: high
• mortality: none
Interference with research
Physiology
• interference with studies involving eyes, salivary and lacremal glands or respiratory system (Jacoby, 1986)
• reduced reproduction and growth rates (Utsumi et al., 1980)
• impairing functions such as olfaction and chemoreception for up to two weeks postexposure (Bihun and Percy, 1995)
Immunology
• reduction of interleukin production in alveolar macrophages (Boschert et al., 1988)
• causes increase of localized graft-vs.-host disease in salivary and lacrimal glands
after bone marrow transplant (Rossie et al., 1988)
Infectiology
• increased adherence of Mycoplasma pulmonis in tracheas of infected rats (Schoeb
et al., 1993)
• enhances lower respiratory tract disease in rats following Mycoplasma pulmonis infection (Schunk et al., 1995)
Oncology
• reduction of epidermal growth factor in submaxillary salivary gland (Percy et al.,
1988)
• causes higher prevalence of anterior pituitary tumors in male F344/NCr rats (Rao
et al., 1989)
References
Bihun, C. G., and D. H. Percy. 1995. Morphologic changes in the nasal cavity associated with sialodacryoadenitis virus infection in the Wistar rat. Vet. Pathol. 32:1-10.
Boschert, K.R., T.R. Schoeb, D.B. Chandler, and D.L. Dillehay. 1988. Inhibition of
phagocytosis and interleukin-1 production in pulmonary macrophages from rats with
sialodacryoadenitis virus infection. J. Leukocyte Biol. 44:87-92
Hajjar, A. M., R. F. DiGiacomo, J. K. Carpenter, S. A. Bingel, and T. C. Moazed. 1991.
Chronic sialodacryoadenitis virus (SDAV) infection in athymic rats. Lab. Anim. Sci.
41:22-25.
Jacoby, R.O. 1986. Rat coronavirus. In Viral and mycoplasmal infections of laboratory
rodents. p. 625-638. In P. N. Bhatt, R. O. Jacoby, A. C. Morse, III and A. E. New
(eds.), Viral and mycoplasmal infection of laboratory rodents: Effects on biomedical
research. Academic Press, Orlando.
Percy, D. H., M. A. Hayes, T. E. Kocal, and Z. W. Wojcinski. 1988. Depletion of salivary gland epidermal growth factor by sialodacryoadenitis virus infection in the Wistar
rat. Vet. Pathol. 25:183-192.
Rao, G. N., J. K. Haseman, and J. Edmondson. 1989. Influence of viral infections on
body weight, survival, and tumor prevalence in Fischer 344/NCr rats on two-year studies. Lab. Anim. Sci. 39:389-393.
Rossie, K. M., J. F. Sheridan, S. W. Barthold, and P. J. Tutschka. 1988. Graft-versushost disease and sialodacryoadenitis viral infection in bone marrow transplanted
rats. Transplantation 45:1012-1016.
Schoeb, T. R., M. M. Juliana, P. W. Nichols, J. K. Davis, and J. R. Lindsey. 1993. Effects of viral and mycoplasmal infections, ammonia exposure, vitamin A deficiency,
host age, and organism strain on adherence of Mycoplasma pulmonis in cultured rat
tracheas. Lab. Anim. Sci. 43:417-424.
Schunk, M. K., D. H. Percy, and S. Rosendal. 1995. Effect of time of exposure to rat
coronavirus and Mycoplasma pulmonis on respiratory tract lesions in the Wistar rat.
Can. J. Vet. Res. 59:60-66.
Utsumi, K., T. Ishikawa, T. Maeda, S. Shimizu, H. Tatsumi, and K. Fujiwara. 1980.
Infectious sialodacryoadenitis and rat breeding. Lab. Anim. 14:303-307.
Weir, E. C., R. O. Jacoby, F. X. Paturzo, E. A. Johnson, and R. B. Ardito. 1990. Persistence of sialodacryoadenitis virus in athymic rats. Lab. Anim. Sci. 40:138-143.
Author: Felix R. Homberger
Mouse Hepatitis Virus
Host species
• mouse
Organotropism
• polytropic strains: liver, brain, lymphoid tissue, (other organs)
• enterotropic strains: intestine, lymphoid tissue
Clinical disease
• inapparent in immunocompetent adults
• diarrhea and death in neonates (epizootic infection)
• wasting disease in immunodeficient mice
Pathology
• polytropic strains: acute necrosis and syncytia formation in liver, spleen and lymphoid tissue; necrotizing encephalitis with demyelinisation and syncytia formation
• enterotropic strains: villus attenuation, enteroytic syncytia and mucosa necrosis of
the terminal small intestine, the cecum and the ascending colon
Morbidity and mortality
• usually 100% of animals are infected
• mortality close to 100% in neonates (all virus strains, epizootic infection) and in immunodeficient mice (polytropic strains)
• mortality 0% (or very low) in all other cases
Interference with research
Oncology
• Contamination of transplantable tumors (Nicklas et al., 1993)
• abnormal tumor invasion pattern, abnormal tumor passage intervals, spontaneous
regression or oncolysis of normally stable tumors (Akimaru et al., 1981; Braunsteiner and Friend, 1954; Fox et al., 1977; Manaker et al., 1961; Nelson, 1959)
• rejection of human xenografts (Kyriazis et al. 1979)
• altered response to chemical carcinogens (Barthold, 1986a)
Infectiology
• Confusion about origin of virus isolates: Tettnang (Smith et al., 1983), multiple
sclerosis (Gerdes et al., 1981), puffinosis (Nuttall and Harrap, 1982)
• Reduced susceptibility for viral infections (PVM, Sendai ) (Carrano et al., 1984)
• Potentiation of subclinial MHV infections by urethane and methylformamide
(Braunsteiner and Friend, 1954), halothane (Moudgil, 1973), transplantation of tumors (Barthold, 1986b), concurrent infection with Eperythrozoon coccoides (Kraft,
1982)
• enhances resistance to Salmonella typhimurium in mice by inducing suppression of
bacterial growth (Fallon et al., 1991).
Immunology
• immunodepression and immunostimulation depending on the time of infection (Virelizier et al., 1976).
• MHV replicates in macrophages and with or without lysis in both B and T lymphocytes (Bang and Warwick, 1960; de Souza and Smith, 1991; Lamontage et al.,
1989).
• enhanced and suppressed macrophage function (Boorman et al., 1982; Dempsey et
al., 1986) and dysfunction of T and B cells (Casebolt et al., 1987; Cook-Mills et al.,
1992; de Souza et al., 1991; Smith et al., 1991).
• activation of natural killer (NK) cells and alteration of the interferon responsiveness of infected mice (Schindler et al., 1982; Virelizier et al., 1976).
• reduced levels of cytokines, interleukins and gamma interferon in spleen cells (de
Souza et al., 1991).
• recovered mice have complete or partial protection against T cell dysfunctions when
re-infected with different strains of MHV (Smith et al., 1992).
• macrophage dysfunctions continue in MHV-recovered mice (Boorman et al., 1982)
• MHV infection can durably modify unrelated T cell responses that are initiated at
the time of infection (Coutelier et al., 1991).
• permanent decrease of skin graft rejection and T cell dependent antibody responses
after recovering from MHV-A59 infection (Cray et al., 1993).
• enhancement of concomitant autoimmune reactions (Lardans et al., 1996)
Physiology
• alteration of liver enzyme levels, patterns of protein synthesis and other biochemical markers (Barthold, 1986a; Lucchiari et al., 1992.; Piazza, 1969)
• induction of alpha-fetoprotein (Kiuchi et al., 1974) and increase of iron uptake (Tiensiwakul and Husain, 1979)
• changes in peripheral blood such as anemia, thrombocytopenia, leukopenia and increased monocyte procoagulant activity (Levy et al., 1981; Piazza et al., 1965).
• decrease of the incidence of diabetes in non-obese diabetic mice (Wilberz et al.,
1991)
Reproductive technology
• persistent contamination of embryonic stem (ES) cells without diminishing their
pluripotency (Okumura et al., 1996)
References
Akimaru, K., G. M. Stuhlmiller, and H. F. Seigler. 1981. Influence of mouse hepatitis virus
on the growth of human melanoma in the peritoneal cavity of the athymic mouse. J. Surg.
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Bang, F. B., and A. Warwick. 1960. Mouse macrophages as host cells for mouse hepatitis
virus and the genetic basis of their susceptibility. Proc. Natl. Acad. Sci. USA 46:1065-1075.
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Barthold, S. W. 1986b. Mouse hepatitis virus biology and epizootiology, p. 571-601. In P. N.
Bhatt, R. O. Jacoby, A. C. Morse, III and A. E. New (eds.), Viral and mycoplasmal infection
of laboratory rodents: Effects on biomedical research. Academic Press, Orlando.
Boorman, G. A., M. I. Luster, J. H. Dean, M. L. Cambell, L. A. Lauer, F. A. Talley, R. E.
Wilson, and M. J. Collins. 1982. Peritoneal and macrophage alterations caused by naturally occurring mouse hepatitis virus. Am. J. Pathol. 106:110-117.
Braunsteiner, H., and C. Friend. 1954. Viral hepatitis associated with transplantable
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Author: F. Homberger
Rotaviruses
The genus rotavirus is divided into a number of groups between which antigenicity is distinct (Bridger 1994)
Host species
• laboratory animals, particularly mice, rats, and rabbits (Sheridan & Vonderfecht
1986, Vonderfecht 1986, National Research Council 1991, Harkness & Wagner
1995)
• wide range of domestic and wild mammalian animals, birds, humans
Properties
• murine rotavirus is stable at –70oC but unstable at –24, 4, and 37oC; not resistant
to environmental conditions (Sheridan & Vonderfecht 1986, National Research
Council 1991, Vonderfecht 1994)
• rotaviruses tend to be stable at low pH and labile at pH values above 10.0
Strain susceptibility
• naive BALB/c mice of all ages are susceptible to murine rotavirus; other strains of
mice, such as C57BL/6, are much more resistant to infection with murine rotavirus
as adults (Ward & McNeal 1999)
• Prkdcscid mice may become persistently infected with rotavirus (Riepenhoff-Talty
et al. 1987, Franco & Greenberg 1999)
Organotropism
• fenterotropic
• hepatobiliarytropic in heterologously infected mice (Uhnoo et al. 1990b, Petersen et
al. 1998)
Clinical disease
• usually inapparent in adults
• major cause of acute diarrhea in infants and in the young of other mammalian and
avian species
• the natural disease in mice is caused by group A rotaviruses and has been known
as "epizootic diarrhea of infant mice" (EDIM); the susceptibility to EDIM is dependent on the immunological status and the age of the host, and peaks between 3-14
days of age (Sheridan & Vonderfecht 1986, National Research Council 1991, Harkness & Wagner 1995, Ball et al. 1996)
• the natural disease in rats has been named "infectious diarrhea of infant rats"
(IDIR) and is caused by a group B rotavirus; the clinical course of IDIR is similar to
that of EDIM (Vonderfecht 1986, National Research Council 1991, Harkness &
Wagner 1995)
• rabbits ranging from 1-12 weeks of age may exhibit clinical signs of diarrhea following infection with group A rotaviruses (Thouless et al.1988, Vonderfecht 1994)
Pathology
• histopathologic changes in the intestine are confined to the small intestine and
most prominent at the tips of villi; lesions include swelling and vacuolation of epithelial cells, formation of epithelial syncytial cells, intracytoplasmic inclusion bodies
in the epithelial cells, epithelial cell necrosis, sloughing of epithelial cells into the
intestinal lumen, villus atrophy and blunting, edema and mild inflammation in the
lamina propria of villi (Sheridan & Vonderfecht 1986, Vonderfecht 1986, National
Research Council 1991, Salim et al. 1995, Ciarlet et al. 1998)
• hepatitis, cholangitis, and biliary atresia in infant Balb/c mice after experimental
infection with rhesus rotavirus (Uhnoo et al. 1990b, Petersen et al. 1998)
• Morbidity and mortality
• rotaviruses are highly contagious and infection is easily spread within a group
(Kraft 1958)
• high morbidity (in the young) and low mortality; mortality is more common in infected rabbits (Vonderfecht 1994)
Zoonotic relevance
• animal-to-human transmission may occur (Nakagomi et al. 1992, Shirane & Nakagomi 1994) but does not appear to be common
Interference with research
Physiology
• rotaviruses bind to the neutral glycosphingolipid gangliotetraosylceramide (Willoughby et al. 1990) and to O-linked sialylglycoconjugates and sialomucins (Willoughby 1993)
• malnutrition and other dietary alterations may enhance murine rotavirus infection
(Morrey et al. 1984, Noble et al. 1983, Uhnoo et al. 1990a, Sagher et al. 1991)
• rotaviruses induce changes in the microcirculation of intestinal villi of neonatal
mice (Osborne et al. 1991)
• rotavirus infection alters intestinal absorption (Davidsson et al. 1977, Graham et
al. 1984, Heyman et al. 1987, Ijaz et al. 1987, Salim et al. 1995, Katyal et al. 1999)
and intestinal enzyme profiles (Collins et al. 1988, 1990, Jourdan et al. 1998, Katyal et al. 1999)
• intestinal fluid and electrolyte secretion is enhanced through the effects of a viral
enterotoxin NSP4 (Ball et al. 1996, Estes & Morris 1999) and by activation of the
enteric nervous system (Lundgren et al. 2000)
Cell biology
• rotavirus infection causes alterations in the polarized sorting of neuronal proteins
(Weclewicz et al. 1993)
• NSP4 increases intracellular calcium levels by release from the endoplasmic reticulum (Tian et al. 1994, 1995, Ball et al. 1996)
• NSP4 alters plasma membrane permeability and may facilitate cell death (Tian et
al. 1996, Newton et al. 1997)
Immunology
• rotavirus infection causes recruitment and activation of CD4+ and CD8+ T cells
(Offit & Dudzik 1989, Offit et al. 1992, McNeal et al. 1997, Rott et al. 1997) and a
vigorous mucosal IgA response (Merchant et al. 1991, Coffin et al. 1995); resolution
of rotavirus infection is due to both T (particularly CD8+ cells) and B cells, while
protection against rotavirus is primarily dependent on antibodies (Ward 1996,
Feng et al. 1997, McNeal et al. 1997, Franco & Greenberg 1999)
• rotavirus infection induces a mixed Th1/Th2 pattern of cytokine production (IFN-g,
IL-5, IL-10) by mouse spleen cells (Fromantin et al. 1998)
• rotavirus infection leads to increased mRNA for several C-C and C-X-C chemokines
and interferon-b in the mouse small intestine (Rollo et al. 1999)
• Interactions with other infectious agents
• a synergistic pathogenic effect between rotavirus and Escherichia coli occurs in infant mice (Newsome & Coney 1985) and weanling rabbits (Thouless et al. 1996)
• infection of human enterocyte-like cells with rotavirus enhances invasiveness of
Yersinia enterocolitica and Y. pseudotuberculosis (Di Biase et al. 2000)
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Author: Dr. Michael Mähler, Hannover
Sendai Virus
Host species
• mouse, rat, hamster, (guinea pig)
Organotropism
• respiratory tract
Clinical disease
• usually inapparent
• severe clinical disease with complicating infections (M. pulmonis, CAR bacillus)
Pathology
• focal/segmental necrotizing inflammation of respiratory epithilium
• suppurative or necrotizing bronchitis and bronchiolitis
• foci of interstitial pneumonia
Morbidity and mortality
• up to 100% of a colony infected
• morbidity and mortality depending on host strain (Brownstein and Winkler, 1986,
Parker et al., 1978, Percy et al., 1994, Steward and Tucker, 1978)
Interference with research
Physiology
• Sendai virus infection in guinea pigs and rats enhances airway responsiveness to
acetylcholine and substance P (Elwood et al., 1993; Yamawaki et al., 1995)
• Sendai virus infection aggravates the airway damage in rat lung allografts with
chronic rejection (Winter et al., 1994)
• Sendai virus infection reduces the life span of the H-2d and H-2b genotypes B10
congenic mice (Yunis and Salazar, 1993)
Pathology
• increased number of mitotic cells in bronchial epithelium and in lung parenchyma
(Richter, 1970)
• increase in bronchiolar mast cells persists for months after infection (Sorden and
Castleman, 1995)
• Sendai virus nucleoprotein gene is detectable in the olfactory bulbs of intranasally
infected mice for at least 168 days post-infection (p.i.) by PCR (Mori et al., 1995)
Immunology
• increase in natural killer cell mediated cytotoxicity (Clark et al., 1979)
• induction of tumor necrosis factor and other cytokines (Aderka et al., 1986; Costas
et al., 1993; Mo et al.,1995; Uhl et al., 1996)
• long term effect on the immune system (55 out of 63 parameters are affected (Kay,
1978)
• Sendai virus infection of C57BL/6 mice elicits a strong CD4+ and CD8+ T-cell response in the respiratory tract (Cole et al., 1994)
• infected mice have enhanced numbers of cytotoxic T-lymphocyte precursors ( > 20x
background) for life (Doherty et al., 1994)
• impairment of macrophage function causing delay in wound healing (Kenyon, 1983)
Infectiology
• decrease of pulmonary bacterial clearance ( Degre and Solberg, 1971)
• interaction with bacterial pathogens (Jakab, 1981)
Oncology
• production of polyploid variants of tumor cells with increased chromosome numbers
and reduced tumourigenicity (Matsuya et al., 1978)
• reduced transplantability of hamster tumor cells in combination with augmented
cell-mediated immunity (Ogura et al., 1980; Yamada and Hatano, 1972)
• altered host responce to transplantable tumors (Wheelock, 1966, 1967; Collins and
Parker, 1972; Matsuya et al., 1978)
• strong influence on chemically induced carcinogenesis (Peck et al., 1983)
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carcinogenesis in strain A mice. Lab. Anim. Sci. 33:154-156.
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mast cells in Brown Norway rats are associated with both local mast cell proliferation
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mice: Reciprocal interference between Sendai virus and Friend leukemia in DBA/2
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Natl. Cancer Inst. 38:771-778.
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Author: F. Homberger
Encephalitozoon cuniculi
Host species
• Rabbit (principal host), guinea pig, hamster, rat, mouse
• Dog, some wild and zoo animals
Organotropism
• Brain/Spinal cord
• Kidney
• Liver
Clinical disease
• Usually inapparent
• Occasionally (most often seen in rabbits) neurological disturbances such as torticollis
Morbidity and mortality
• Because of the subclinical nature and multiple routes of transmission, undetected
infection can persist in a colony with up to 75% infected animals.
• Morbidity and mortality depend on host strain, generally very low with only single
cases of clinical disease in immunocompetent animals.
• Different susceptibility to E. cuniculi in different inbred strains of mice (Niederkorn et al., 1981).
Zoonotic relevance
• Spores are excreted via urine, infection of humans is possible. However, only rare
cases of human disease have been reported, and susceptibility of man to E. cuniculi
is not well known.
Interference with research
Pathology
• Nervous system: multifocal parenchymal and perivascular cell infiltrations, granulomas with pseudocysts, occasional necrotic foci, occasional meningeal Iymphocytic
infiltrates.
• Kidneys: multifocal interstitial nephritis, occasional granulomas with pseudocysts.
• Liver: occasional granulomas.
• In immunocompromised hosts possibly aggregates of pseudocysts with minimal inflammatory reaction in various organs.
• 2-3 weeks after intraperitoneal inoculation in mice, animals develop ascites.
Immunology
• Uptake of E. cuniculi by host macrophages (Cox et al. 1979; Weidner 1975).
• Murine peritoneal macrophages can be activated with LPS + IFN-gamma to kill E.
cuniculi in vitro (Didier and Shadduck,1994).
• T-cells may act by releasing lymphokines to activate macrophages which can then
kill the parasite (Schmidt and Shadduck,1984).
• he lpr (lymphoproliferation) gene does not influence susceptibility to murine encephalitozoonosis (Liu and Shadduck,1988).
• Spontaneous hypergammaglobulinemia in MRL/MPJ mice remains unchanged by
E. cuniculi (Liu and Shadduck, 1988).
• During early stages of E. cuniculi infection, murine spleen cells express significantly lower blastogenic responses to T-cell mitogens than uninfected mice (Didier
and Shadduck, 1988).
• In neonatal dogs, a depressed T-lymphocyte response to blastogenic stimuli, together with hypergammaglobulinemia (IgG, IgM) was found (Szabo and Shadduck,
1987). In rodents, transient suppression of cell mediated immune responses and no
evidence of hypergammaglobulinemia, thus indicating species specificity of immune effects.
• Rabbits infected with E. cuniculi show inconsistent response to neural device biomaterial and are thus inadequate test systems for tissue compatibility testing of
such materials (Ansbacher et al.,1988).
• In rabbits naturally infected with E. cuniculi, the immune response to the immunogen Brucella aboffus is altered (elevated IgM, depressed IgG) (Cox and Gallichio,
1978).
Infectiology
• Mice infected with E. cuniculi are more resistant to intracerebral inoculation with
Chlamydia trachomatis than non-infected mice (Lepine and Sautter, 1949).
Oncology
• Infected rats which were injected with sarcoma cells had a 50% longer survival
than controls (Petri, 1965).
• In infected mice, the growth of several transplantable tumors was reduced and the
life-span of the host was prolonged (Arison et al., 1966).
References
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Cox, J. C. 1977. Altered immune responsiveness associated with Encephalitozoon cuniculi
infection in rabbits. Infect. Immun. 15:392-395.
Cox, J. C. and H. A. Gallichio. 1978. Serological and histological studies on adult rabbits
with recent, naturally-acquired encephalitozoonosis. Res. Vet. Sci. 24:260-261.
Cox, J.C., R. C. Hamilton and H. D. Attwood. 1979. An investigation of the route and progression of Encephalitozoon cuniculi infection in adult rabbits. J. Protozool. 26:260-265.
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experimental Encephalitozoon cuniculi infection in BALB/c mice. Lab. Anim. Sci. 38:680684.
Didier, E. S. and J. A. Shadduck. 1994. IFN-y and LPS induce murine macrophages to kill
Encephalitozoon in vitro. J. Eukaryotic Microbiol. 41:34S.
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and immunocompetent mice. Lab. Anim. 14:189-192.
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commercial barrier-maintained rabbit breeding colony. Lab. Anim. 25:287-290.
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of age and mode of transmission on occurrence of infection. Lab. Anim. Sci. 38:675-679
Liu, J. J. and J. A. Shadduck. 1988. Encephalitozoon cuniculi infection in MRL/MPJ-LPR
(lymphoproliferation) mice. Lab. Anim. Sci. 38:685-688.
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Author: G. Pohlmeyer / M. Mähler
Toxoplasma gondii
(description for intermediate hosts)
Host species
• Cat (definitive host) (Jones 1973, Wong & Remington 1993)
• All laboratory and domestic animals, birds and humans (intermediate hosts)
• Differential host species susceptibility is reviewed by Innes (1997)
Organotropism
• Central nervous system (Jones 1973, Wong & Remington 1993)
• Muscle and other organs may also be involved.
Clinical disease
• Usually inapparent
• Occasionally neurological symptoms and/or febrile disease
Morbidity and mortality
• Largely depending on the route of infection, parasite strain and dose, and the immunologic state of the host (Dubey & Frenkel 1973, Fernando 1982, Suzuki et al.
1988)
• Clinical disease most likely in young animals or immunocompromised hosts
• Resistance to acute infection and formation of cysts in the brain of mice are genetically controlled (Araujo et al. 1976, Williams et al. 1978).
• Differences in a gene(s) within the H-2D region correlate with resistance or susceptibility to development of Toxoplasma (T.) encephalitis in mice (Jones & Erb 1985,
Suzuki et al. 1991, Blackwell et al. 1993).
• Age, gender, and pregnancy influence susceptibility to T. gondii infection in mice
(Johnson et al. 1995, Thouvenin et al. 1997, Walker et al. 1997).
Zoonotic relevance
• Transmission to humans from other intermediate hosts only by ingestion of uncooked tissues containing T. gondii (Dubey 1994).
Interference with research
Physiology
• Mice infected with T. gondii exhibit ovarian dysfunction with uterine atrophy and
thyroidal dysfunction (decline in serum thyroxine levels), probably due to impaired
release of hypothalamic releasing hormones (Stahl et al. 1995a, 1995b, Stahl et al.
1998)
• T. gondii infection increases toxicity of some drugs (e.g., neostigmine) (Starec et al.
1997)
Pathology
• Central nervous system: organisms intra- or extracellular in the neuropil, within
granulomatous encephalitis, glial nodules or perivascular infiltration; occasionally
accompanied by meningitis and/or scattered neuronal degeneration; occasionally
fibrinoid necrosis of vessel walls in association with microthrombi in the centres of
small necrotic foci (Sasaki et al. 1981, Hay et al. 1984, Kittas et al. 1984, Ferguson
& Hutchinson 1987, Ferguson et al. 1991).
• Lesions in immunocompromised hosts may lack inflammatory infiltrates and solely
consist of small necrotic foci and scattered cysts (Buxton 1980, Johnson 1992)
• Muscle and other organs may be involved with necrotic foci, granulomas and pseudocysts
Immunology
• Acute and chronic T. gondii infection modulate the immune responses in mice
(Nguyen et al. 1998)
• T. gondii is able to induce transient immune down-regulation (Channon & Kasper
1996, Denkers et al. 1996, Khan et al. 1996)
• T. gondii-infected cells are resistant to multiple inducers of apoptosis (Nash et al.
1998).
• Gamma delta T cells induce expression of heat shock protein 65 in macrophages of
mice infected with T. gondii, thereby preventing the apoptosis of infected macrophages (Hisaeda et al. 1997).
• Intracellular T. gondii interferes with the MHC class I and class II antigen presentation pathway of murine macrophages (Luder et al. 1998).
• CD4+ and CD8+ T lymphocytes appear to act in concert to prevent reactivation of
chronic T. gondii infection (Brown & McLeod 1990, Araujo 1991, Gazzinelli et al.
1992c).
• NK cell activity and production of IFN-g are increased during the course of T. gondii infection in mice; IFN-g plays a critical role in preventing cyst rupture and toxoplasmic encephalitis (Hauser et al. 1982, Suzuki et al. 1989, Sher et al. 1993,
Hunter et al. 1994a).
• Cytokine levels are elevated in infected humans and in murine models of toxoplasmosis. Overview about immunopathology of T. gondii infection: Beaman et al. 1992,
Gazzinelli et al. 1993, Subauste & Remington 1993, Hunter & Remington 1994,
Hunter et al. 1994b.
• IL-12 is crucial for the generation of both innate resistance mechanisms during the
acute phase of infection and T cell-dependent acquired immunity during the
chronic phase (Johnson & Sayles, 1997).
• Various other cytokines, such as IFN-b, IL-1, IL-4, IL-6, IL-10, TGF-b, and TNF-a,
are implicated in the pathogenesis of T. gondii infection (Chang et al. 1990, Orellana et al. 1991, Gazinelli et al. 1992b, Sher et al. 1993, Hunter et al. 1995a,
1995b, Roberts et al. 1996, Bessieres et al. 1997, Neyer et al. 1997, Deckert-Schluter et al. 1998, Jebbari et al. 1998).
• Inducible nitric oxide is essential for host control of chronic T. gondii infection
(Scharton-Kersten et al. 1997).
• Innate resistance mechanisms during T. gondii infection are reviewed by Alexander
et al. (1997); T cell-mediated immunity during T. gondii infection is reviewed by
Denkers & Gazzinelli (1998).
Infectiology
• Macrophage clearance and killing of Listeria monocytogenes and Salmonella typhimurium are decreased in mice infected with T. gondii (Wing et al. 1983)
• Infection with murine leukemia virus may lead to reactivation of chronic T. gondii
infection (Gazzinelli et al. 1992a, Watanabe et al. 1993)
• Infection with murine cytomegalovirus results in reactivation of Toxoplasma pneumonia (Goetz & Pomeroy 1996)
• Mice infected with T. gondii are resistant to proliferation of Cryptococcus neoformans cells in the brain (Aguirre et al. 1996)
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Wong SY, Remington JS (1993) Biology of Toxoplasma gondii. AIDS 7, 299-316
Author: G. Pohlmeyer / M. Mähler
Pneumocystis carinii Host species
• Laboratory animals (Smulian & Walzer 1992)
• Wide range of domestic animals, monkeys, humans
Organotropism
• Lungs
• Occasionally other organs or generalization to eyes, skin etc.
Clinical disease
• Inapparent in immunocompetent host
• Slowly progressive chronic pneumonia with weight loss in immunocompromised
host
Morbidity and mortality
• Cconventionally bred colonies may be persistently infected because of subclinical
nature in immunocompetent hosts (Frenkel et al. 1966).
• High morbidity and mortality with chronic progressive pneumonia in immunosuppressed animals
Zoonotic relevance
• Pneumocystis (P.) carinii is not universally transmissible between mammalian species (Gigliotti et al. 1993).
• Respiratory mode of transmission (Hughes 1982)
• Most common opportunistic infection and leading cause of morbidity and mortality
in AIDS patients
Interference with research
Physiology
• P. carinii pneumonia leads to alterations in compliance and lung mechanisms
(Brun-Pascaud et al. 1985, Stokes et al. 1986).
• P. carinii may alter the amount and type of surfactant produced: P. carinii pneumonia in rats leads to a decrease in surfactant phospholipids in bronchoalveolar lavage (Kernbaum et al. 1983, Sheehan et al. 1986). P. carinii organisms can directly
inhibit secrection of phosphatidylcholin from type II cells (Rice et al. 1993). Broncho-alveolar lavage phosphatidylglycerol is reduced in rats with P. carinii pneumonia (Su et al. 1996). Surfactant protein-A levels increase during P. carinii pneumonia in the rat (Phelps et al. 1996).
• Attachment of P. carinii to alveolar macrophages occurs by a fibronectin- and calcium dependent mechanism, but does not trigger a phagocytic response (Pottratz &
Martin 1990a, 1990b). P. carinii glycoprotein A binds macrophage mannose receptors, thereby mediating binding and uptake of P. carinii by alveolar macrophages
(Ezekowitz et al. 1992, O’Riordan et al. 1995). Surfactant protein A can function as
a ligand between P. carinii and alveolar macrophages (Williams et al. 1996).
•Attachment of P. carinii to type I pneumocytes leads to their degeneration and to
proliferation of type II pneumocytes.
• Following attachment of P. carinii to type I cells, surface glycocalyx is decreased
and alveolar-capillary permeability is increased (Lanken et al. 1980, Yoneda &
Walzer 1980, 1981, 1984). As a consequence of dysplasia and disruption of the epithelium, underlying material gains access to the alveolar space and impairs normal
lung function.
• P. carinii attachment increases expression of fibronectin-binding integrins on cultured lung cells (Pottratz et al. 1994).
• P. carinii and IFN-g induce rat alveolar macrophages to produce nitric oxide (Sherman et al. 1992).
• The mitochondrial ATPase 6 gene is upregulated in P. carinii-infected rat lungs (Asnicar et al. 1996).
• P. carinii infection alters GTP-binding proteins in the lung (Oz & Hughes 1997).
• P. carinii inhibits cyclin-dependent kinase activity in lung epithelial cells (Limper
et al. 1998).
• Fibrinogen expression is induced in the lung epithelium during P. carinii pneumonia (Simpson-Haidaris et al. 1998).
Pathology
• Slight infection: multifocal alveolar aggregates of cysts and interstitial/perivascular
non-purulent infiltration (Walzer et al. 1980, Chen et al. 1990)
• Severe infection: consolidated lungs; extensive lung areas involved with alveolar
aggregates of cysts (eosinophilic, honeycombed material), proliferation of type II
pneumocytes and severe interstitial fibrosis
• Extrapulmonary manifestation of P. carinii infection by hematogenous or lymphatic
spread is possible; major sites are lymph nodes, bone marrow, liver, and spleen,
characterized by eosinophilic honeycombed material with inflammatory response.
• Multinucleated giant cells in murine P. carinii pneumonia (Hanano et al. 1996)
Immunology
• High risk for all congenitally immunodeficient hosts and for experimental models of
immunosuppression.
• P. carinii from different host species are immunologically distinct (Gigliotti &
Harmsen 1997).
• P. carinii induces activating and inhibitory innate cellular immune response mechanisms (Warschkau et al. 1998).
• Cellular immunity is important for protection against P. carinii pneumonia (Furuta
et al. 1984, 1985).
• P. carinii-reactive CD4+ lymphocytes may contribute to the host's response via secretion of macrophage-activating cytokines (IFN-g and others) as well as by the
production of signals that induce foster expansion of the antibody-forming pool of B
cells and cytotoxic CD8+ lymphocytes (Beck et al. 1993).
• Protective immunity against P. carinii is mediated by CD4+ T cells (reviewed by
Hanano & Kaufmann 1998).
• Neutrophils, alveolar type II epithelial cells, B cells, CD8+ lymphocytes, antibodies
and cytokines, such as IFN-g and TNF, participate in host effector mechanisms
against P. carinii (Masur & Jones 1978, Von Behren & Pesanti 1978, Shear et al.
1989, Pesanti 1989, 1991, Chen et al. 1992, Beck et al. 1996, Garvy et al. 1997,
Kolls et al. 1997 Marcotte et al. 1996).
• P. carinii induces TNF-a production from monocyte and macrophage cultures with a
peak within 8 h of incubation (Tamburrini et al. 1991).
• P. carinii glycoprotein A stimulates IL-8 production and inflammatory cell activation in alveolar macrophages and cultured monocytes (Lipschik et al. 1996).
• P. carinii induces expression of ICAM-1 and IL-6 in lung epithelial cells (Yu & Limper 1997 Pottratz et al. 1998).
Infectiology
• Neutrophils in bacterial pneumonia may participate in host effector mechanisms
against P. carinii (Pesanti 1982).
References
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L1103- 1111
Author: Dr Gabi Pohlmeyer-Esch / Dr. M. Mähler
Staphylococcus aureus (subsp. aureus)
Host species
• wide range of domestic and wild mammalian animals, birds, humans
• various species of laboratory animals (National Research Council 1991, Shimizu 1994,
Harkness & Wagner 1995, Percy & Barthold 2007)
Properties
• S. aureus exists in the environment such as dust, water, food or on food equipment and
environmental surfaces, and it is relatively resistant to a variety of environmental conditions
such as drying, UV light, and heat (National Research Council 1991, Shimizu 1994,
Harkness & Wagner 1995). This environmental resistance and the broad host spectrum
make it difficult to control spread of infection.
• S. aureus easily develops antibiotic resistance (Shimizu 1994, Winn et al. 2006). This is
particularly a problem in S. aureus strains derived from hospitalized humans. They are
typically resistant to multiple antibiotics including methicillin and oxacillin. The prevalence
of such strains is lower in the community and in animal facilities, because antibiotic
selective pressure is much lower than in hospitals.
Organotropism
• common inhabitant of the skin and mucous membranes (nasopharynx, lower intestinal tract,
lower genital tract)
• entry into the body occurs most probably through breaks in the oral mucosa or skin
Clinical disease
• animals and human carriers usually remain asymptomatic (National Research Council 1991,
Shimizu 1994, Harkness & Wagner 1995, Winn et al. 2006, Percy & Barthold 2007);
clinical disease is common in immunocompromised hosts
• clinical signs (other than sudden death from pneumonia, septicaemia, or toxaemia) in
laboratory animals include fever, anorexia, depression, various forms of dermatitis, foot
swelling, reddening of the conjunctiva, lacrimation, subcutaneous lumps, enlarged
mammary glands, and purulent discharge
• skin lesions are frequently accompanied by pruritus resulting in scratching and selfmutilation
Pathology
A variety of distinct disease processes have been reported in laboratory animals (National
Research Council 1991, Shimizu 1994, Harkness & Wagner 1995, Percy & Barthold 2007),
including the following:
• mouse: suppurative or ulcerative dermatitis, furunculosis, conjunctivitis, facial abscesses,
botryomycotic granulomas, subcutaneous abscesses, preputial gland abscesses,
bulbourethral gland abscesses, balanoposthitis, urinary cystitis
• rat: ulcerative dermatitis, pododermatitis, keratoconjunctivitis, panophthalmitis,
subcutaneous abscesses
• guinea pig: exfoliative dermatitis, pododermatitis ("bumblefoot"), conjunctivitis,
pneumonia, mastitis, osteoarthritis
• rabbit: conjunctivitis, subcutaneous abscesses, bronchopneumonia, lymphadenitis, mastitis
• hamster: dermal abscesses
• Mongolian gerbil: dermatitis ("sore nose").
In humans, a variety of suppurative inflammatory conditions and toxinoses are found (Winn
et al. 2006):
• suppurative inflammation: skin lesions (e.g. furunculosis, impetigo), pneumonia, mastitis,
phlebitis, meningitis, osteomyelitis, endocarditis, etc.
• toxinoses: toxic epidermal necrolysis, toxic shock syndrome, food poisoning.
Morbidity and mortality
Morbidity and mortality are highly variable and influenced by host, bacterial, and
environmental factors:
• strain differences in susceptibility to S. aureus infection and associated disease are found
among immunocompetent mice (Shults et al. 1973, Needham & Cooper 1976, Hong &
Ediger 1978, von Köckritz-Blickwede et al. 2008); e.g. in the latter study, C57BL/6 mice
were the most resistant in terms of control of bacterial growth and survival, A/J, DBA/2,
and BALB/c mice were highly susceptible, and C3H/HeN, CBA, and C57BL/10 mice
exhibited intermediate susceptibility levels
• immunodeficient hosts such as splenectomized or neutrophil-depleted mice (Teixeira et al.
2008, Robertson et al. 2008), athymic nude mice (Sano et al. 1988), iNOS-deficient mice
(McInnes et al. 1998), TLR2-deficient and MyD88-deficient mice (Takeuchi et al. 2000)
are highly susceptible to S. aureus infection or associated disease; likewise, certain mutant
strains of mice without (known) inmmunodeficiency such as mice deficient in urokinasetype plasminogen activator have an increased susceptibility to staphylococcal disease
(Shapiro et al. 1997)
• the genetic background strain may influence outcome of disease in mutant mice such as S.
aureus-triggered sepsis and arthritis in IL-4-deficient mice (Hultgren et al. 1999)
• female and castrated CD-1 mice are more susceptible to infection with certain strains of S.
aureus, suggesting a hormonal influence on resistance (Yanke et al. 2000)
• other contributing host factors are age (Girgis et al. 2004), physical injuries, e.g. as a result
of fighting or surgery, and behavioural dysfunctions such as trichotillomania (Jacoby et al.
2002, Percy & Barthold 2007)
• S. aureus strains can express a diverse arsenal of virulence factors and differ in virulence
(Mizobuchi et al. 1994, Benton et al. 2004, Sibbald et al. 2006)
• predisposing environmental factors include stress, e.g. provoked by experimental
procedures, nutritional deficiencies (Galler et al. 1979, Chew et al. 1985, Wiedermann et al.
1996), concurrent infections, e.g. with mites (Percy & Barthold 2007) or Pseudomonas
aeruginosa (Hendricks et al. 2001), and the prevalence of S. aureus in the environment
Zoonotic relevance
• transmissible between species
• transmission mainly by contact with infected animals or humans and their excretions
• humans are a reservoir: ~20% of people persistently carry S. aureus in the anterior nares,
and ~60% are intermittent carriers (Kluytmans et al. 1997)
Interference with research
S. aureus could principally interfere with research by induction of disease (as described
above). In addition, natural infection with S. aureus could compromise numerous studies
using experimental animal models of S. aureus infection (e.g. models of implant-related
infection, surgical wound infection, infected burn wounds, septic shock, infective
endocarditis, and bone infection). It also has to be considered that S. aureus produces a
variety of biologically active products, including protein A, catalase, coagulase, fibrinolysins,
hyaluronidase, lipases, hemolysins, leucocidin, exfoliatins, enterotoxins, and toxic shock
syndrome toxin (Winn et al. 2006). The effects of these products and their metabolites are
numerous and are not covered by this monograph. The following list provides examples of
potential research complications due to entire S. aureus organisms:
Physiology
• S. aureus induces serum α2-macroglobulin in rats (Jinbo et al. 2001)
• S. aureus causes contractile dysfunction in the mouse heart (Knuefermann et al. 2004) and
aorta (Cartwright et al. 2007)
Pathology
• immunocompromised animals are at increased risk for pathological lesions caused by S.
aureus, e.g. kidney abscesses have been observed in infected rats following treatment with
corticosteroids (Simmons & Simpson 1977)
• inapparent wound infection with S. aureus increases plasma fibrinogen levels, total
leukocyte counts, and wound histology scores in rats (Bradfield et al. 1992)
• S. aureus and its peptidoglycan ameliorate glucocorticoid-induced impaired wound healing
in rats (Chang et al. 1997)
• S. aureus and its peptidoglycan stimulate macrophage recruitment, angiogenesis,
fibroplasia, and collagen accumulation in wounded rats (Kilcullen et al. 1998)
• S. aureus enhances inflammation, endothelial injury, and blood coagulation in mice with
streptozotocin-induced diabetes (Tsao et al. 2006)
• S. aureus elicits marked alterations in the mouse airway proteome during early pneumonia,
including an increase in antimicrobial peptides, opsonins, pro-inflammatory mediators, and
coagulation proteins (Braff et al. 2007, Ventura et al. 2008)
• spontaneous arthritis in MRL/lpr mice is aggravated by S. aureus infection (SalinasCarmona et al. 2009)
Cell biology
• infection with S. aureus induces a pro-inflammatory state in endothelial cells, as determined
by expression of cytokines (Yao et al. 1995, Yao et al. 1996, Söderquist et al. 1998,
Strindhall et al. 2005), Fc receptors (Bengualid et al. 1990), and adhesion molecules
(Strindhall et al. 2002)
• S. aureus enhances expression of Toll-like receptor 2 and MyD88 in microglia (Esen &
Kielian 2006)
• S. aureus induces release of TNF-α and nitric oxide in murine macrophages (Paul-Clark et
al. 2006)
• S. aureus enhances secretion of TNF-α, IL-1β and nitric oxide, and up-regulates expression
of nitric oxide synthase and Toll-like receptor 2 in epididymal epithelial cells (Zhao et al.
2008)
• S. aureus induces expression of IL-6 and IL-12 (Bost et al. 1999), MHC class II molecules
(Schrum et al. 2003a), CD40 (Schrum et al. 2003b), receptor activator of NF-κB ligand and
prostaglandin E2 in osteoblasts (Somayaji et al. 2008)
• S. aureus induces apoptosis in osteoblasts (Tucker et al. 2000)
• S. aureus activates the early response genes c-fos and c-jun and activator protein-1, and
induces proapoptosis genes Bad and Bak in pleural mesothelial cells (Mohammed et al.
2007)
Immunology
• S. aureus inhibits contact sensitivity to oxazolone by activating suppressor B cells in mice
(Benedettini et al. 1984)
• S. aureus induces production of IFN-γ, TNF, and IL-6 in the bloodstreams, spleens, and
kidneys of systemically infected mice (Nakane et al. 1995)
• systemic S. aureus infection induces a Th2 response (IL-4, IL-10) in the spleens of mice
(Sasaki et al. 2000)
Interactions with other infectious agents
• low concentrations of Pseudomonas aeruginosa enhance the ability of S. aureus to cause
infection in a rat model of orthopaedic wounds, while at the same time S. aureus lowers the
rate of Pseudomonas aeruginosa infection (Hendricks et al. 2001)
• S. aureus serves as an iron source for Pseudomonas aeruginosa during in vivo coculture
(Mashburn et al. 2005)
• S. aureus synergizes with Kilham rat virus infection to induce diabetes in BBDR rats (Zipris
et al. 2005)
• co-infection of the cotton rat with S. aureus and influenza A virus results in synergistic
disease and increased induction of both pro- and anti-inflammatory cytokines (IL-1β, IL-6,
IL-10, IFN-γ) (Braun et al. 2007)
Behaviour
• rats with inapparent wound infection show decreased activity in open-field testing and
shorter duration of freezing behaviour (Bradfield et al. 1992)
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Author: Michael Mähler
Date: 16/03/2009
CAR Bacillus
Cilia-associated Respiratory Bacillus
Host species
• wild and laboratory rats (van Zwieten et al. 1980), laboratory mice, African whitetailed rat (Mystromys albicaudatus), rabbits, cattle, goats and swine (MacKenzie et
al. 1981; Matsushita, 1986; Waggie et al. 1987; Shoji et al. 1988; Kurisu et al. 1990;
Shoji-Darkye et al. 1991; Brogden et al. 1993; Hastie et al. 1993; Nietfeld et al.,
1995; Fernández et al. 1996; Caniatti et al. 1998).
Properies
• the organism withstands freezing and thawing, and has been stored at -70ºC and
23ºC for short periods (Ganaway et al. 1985)
Susceptibility
• mice seem to be most sensitive, followed by hamsters, rabbits and guinea pigs.
(Shoji-Darkye et al. 1991)
Organotropism
• respiratory tract
Clinical disease and pathology
• Dyspnoea (Cundiff et al. 1992); respiratory signs such as wheezing, decreased activity and ruffled fur (Matsushita and Joshima, 1989), chronic respiratory disease
(Ganaway et al. 1985, Matsushita 1986)
• Bronchocentric lesions including lymphoid hyperplasia, ectasia of the major airways, mucopurulent exsudation (van Zwieten et al. 1980)
• Suppurative bronchopneumonia and necrotizing interstitial pneumonia and leukocytic infiltration in the lamina propria (Griffith et al. 1988; France 1994; Medina
et al. 1994)
• Laryngeal, tracheal and bronchial epithelia are normally slightly hypertrophic and
hyperplastic, with areas of loss of cilia (Kurisu et al. 1990; Matsushita 1991)
• Squamoid changes in the bronchi, atelectasis, emphysema and bronchiectasis; seldom death (Ganaway et al. 1985; Shoji et al. 1988)
• filamentous bacteria adhered to the respiratory epithelium (Griffith et al. 1988)
• Lesions associated with CAR bacillus may appear as mild peribronchiolar lymphoid
infiltrate, later air ways may become dilated and mucosal hyperplasia could be
found and may progress to metaplasia. (Kendall et al. 1999)
Notice
• CAR bacillus does not grow on cell-free media. Cultivation in cell lines and embryonated eggs is possible (Ganaway et al. 1985)
• Diagnosis is based on identification of the filamentous organism among the cilia of
the respiratiory tract by electron microscopy (MacKenzie et al. 1981), or by using
stains such as Warthin-Statrry, Grocott methenamine silver ( Itoh et al. 1987;
Griffith et al. 1988). Serological tests are available and include ELISA (Ganaway et
al. 1985; Lukas et al. 1987; Shoji et al. 1988) and IFA test (Matsushita et al. 1987).
Morbidity and mortality
• usually inapparent and asymptomatic infections ; low mortality (Ganaway et al.
1985; Shoji et al. 1988; Shoji-Darkye et al. 1991)
• chronic disease
• susceptibility to infection seems to depend on host species (Shoji-Darkye et al.
1991)
Zoonotic potential
• unknown
Interference with research
• Effects on research are not documented. Infected rodents have abnormal tracheobronchial cellular morphology and an increased lung lymphocytic population, raising concerns about their suitability in respiratory, immunology, carcinogenicity
and physiology studies. If ciliary function is altered through ciliastasis or loss of cilia, host respiratory response to pharmacologic or infectious agents might be impaired (Cundiff et al. 1992)
• An infection causes an elevation of gamma interferon (IFN_) and interleukins (IL 4
and IL10). Interleukins are predominat in CAR bacillus induced histologic lesions
in mice, while gamma interferon may have a role in resistance to disease (Kendall
et al., 1999)
References
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1998. Cilia-associated respiratory (CAR) bacillus infection in conventionally reared rabbits. J. Vet. Med. B. 45:363-371.
Cundiff, D. C., C. Besch-Williford, and L. K. Riley. 1992. A review of the cilia-associated respiratory Bacillus. 1992. http://www.criver.com/techdocs/car.html : 1-8
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Mice with Histologic Disease. Comtemporary Topics 4:65-66.
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with respiratory disease in wild rats. Vet. Pathol. 18:836-839.
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Matsushita S. 1991. Ultrastructure of respiratory tract epithelium of rats experimentally
infected with the CAR bacillus: J. Vet. Med. Sci. 53:361-363.
Matsushita S., M. Kashima, and H. Joshima. 1987. Serodiagnosis of cilia-associated respiratory bacillus infection by the indirect immunofluorecence assay technique. Lab. Anim.
21:356-359
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Medina L. V., J. D. Fortman, R. M. Bunte, and B. T. Bennet. 1994. Respiratory disease in a
rat colony: identification of CAR bacillus without other respiratory pathogens by standard
diagnostic screening methods. Lab. Anim. Sci.. 44:521-525.
Nietfeld J. C., C. L. Franklin, L. K. Riley, D. H. Zeman, and B. T. Groff.1995. Colonization
of the tracheal epithelium of pigs by filamentous bacteria resembling cilia-associated respiratory bacillus. J. Vet. Diagn. Invest. 7: 338-342.
Shoji Y., T. Itoh, and N. Kagiyama. 1988. Pathogenesis of two CAR bacillus strains in mice
and rats. Exp. Anim. 37: 447-453
Shoji Y., T. Itoh, and N. Kagiyama. 1988. Enzme-linked immunosorbent assay for detection
of serum antibody to CAR bacillus. Exp. Anim. 37: 69-72
Shoji Y.-Darkye, T. Itoh, and N. Kagiyama. 1991. Pathogenesis of CAR bacillus in rabbits,
guinea pigs, Syrian hamsters, and mice. Lab. Anim. Sci. 41:567-571
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Brunhilde Illgen-Wilcke
Helicobacter spp.
Host and bacterial species
Helicobacter spp. have been isolated from a wide range of laboratory animals (Fox & Lee
1997, Whary & Fox 2004). Various bacterial species have been found, and it is expected
that additional species colonizing laboratory animals will be described in the near future.
In laboratory rodents, the following Helicobacter spp. have been identified:
• mouse: H. muridarum (Lee et al. 1992), ‘H. rappini’ (Schauer et al. 1993), H. hepaticus (Fox et al. 1994), H. bilis (Fox et al. 1995), H. rodentium (Shen et al. 1997), H.
typhlonius (Fox et al. 1999), H. ganmani (Robertson et al. 2001)
• rat: H. muridarum (Lee et al. 1992), H. hepaticus (Riley et al. 1996), H. bilis (Riley
et al. 1996), H. trogontum (Mendes et al. 1996), H. rodentium (Goto et al. 2000), H.
typhlonius (Livingston & Riley 2003)
• hamster: H. cinaedi (Gebhart et al. 1989), H. cholecystus (Franklin et al. 1996), H.
aurati (Patterson et al. 2000), H. mesocricetorum (Simmons et al. 2000)
• Mongolian gerbil: H. bilis (Wang & Fox 1998), H. hepaticus (Goto et al. 2000).
This compilation will focus mainly on H. hepaticus because it is the most prominent of the rodent Helicobacter spp. and is responsible for the most lesions.
Strain susceptibility
Mouse strain differences in disease susceptibility and colonization sites have been reported:
• some mouse strains (including A/JCr, C3H/HeNCr, SJL/NCr, BALB/cAnNCr, and
Prkdcscid/NCr) are highly susceptible to H. hepaticus-associated hepatitits, whereas others (C57BL/6NCr, B6C3F1) are resistant (Ward et al. 1994b)
• in aged male A/JCr mice, H. hepaticus infection is linked to the development of liver tumors (Ward et al. 1994b)
• hepatitis-prone A/JCr mice have lower cecal colonization levels of H. hepaticus than
hepatitis-resistant C57BL/6 mice (Whary et al. 2001)
• several immunodeficient strains of mice (e.g., Foxn1nu, Prkdcscid, Il10tm1Cgn,
Tcratm1Mom) are prone to develop inflammatory bowel disease in response to infections with H. hepaticus (Ward et al. 1996a, Burich et al. 2001), H. bilis (Shomer
et al. 1997, Burich et al. 2001), or H. typhlonius (Fox et al. 1999, Franklin et al.
1999)
Organotropism
• lower intestine (primary site)
• stomach (H. muridarum in mice, H. aurati in hamsters)
• liver (H. hepaticus, H. bilis, and H. ganmani in mice)
• gallbladder (H. cholecystus in hamsters)
Clinical disease
• usually inapparent in immunocompetent rodents
• signs of inflammatory bowel disease in immunodeficient mice and rats include rectal prolapse, mild to severe hemorrhagic or watery diarrhea with resultant perianal dermatitis and weight loss (Ward et al. 1996a, Haines et al. 1998, Shomer et al.
1997, Burich et al. 2001)
Pathology
• chronic active hepatitis with focal necrosis and mixed leukocytic infiltrates in mice
infected with H. hepaticus (Ward et al. 1994a, Ward et al. 1994b, Fox et al. 1996a)
or H. bilis (Fox et al. 1995, Franklin et al. 1998)
• hepatocellular adenoma and carcinoma in H. hepaticus-infected aged A/JCr male
mice (Ward et al. 1994b, Fox et al. 1996a)
• proliferative typhlitis, colitis, and proctitis in immunodeficient mice infected with
H. hepaticus (Ward et al. 1996a, Burich et al. 2001), H. bilis (Shomer et al. 1997,
Burich et al. 2001), or H. typhlonius (Fox et al. 1999, Franklin et al. 1999) and in
immunodeficient rats infected with H. bilis (Haines et al. 1998)
• gastritis in H. muridarum-infected mice (Queiroz et al. 1992)
• cholangiofibrosis and centrilobular pancreatitis in H. cholecystus-infected hamsters
(Franklin et al. 1996)
Morbidity and mortality
• the incidence and severity of Helicobacter-induced disease depend on strain, gender, and age of the host (Ward et al. 1994b, Fox et al. 1996a, Ward et al. 1996a,
Haines et al. 1998, Ihrig et al. 1999, Burich et al. 2001, Livingston et al. 2004
Zoonotic potential
• unclear; some Helicobacter spp. demonstrate zoonotic potential and may cause human disease (e.g., H. cinaedi and ‘H. rappini’ have been isolated from patients with
enteritis and from patients with bacteremia) (De Groote et al. 2000, Andersen
2001)
Interference with research
Physiology
• chronic H. hepaticus infection may lead to elevations in serum levels of alanine
aminotransferase (Fox et al. 1996a, Fox et al. 1996b)
Pathology
• H. hepaticus, H. bilis, and H. typhlonius induce or trigger intestinal inflammation
in various mouse models of inflammatory bowel disease (Cahill et al. 1997, Kullberg et al. 1998, Fox et al. 1999, Chin et al. 2000, Burich et al. 2001); in contrast,
H. hepaticus delays the development of inflammatory bowel disease in multiple
drug resistance-deficient mice (Maggio-Price et al. 2002)
• H. muridarum provokes inflammatory bowel disease in Prkdcscid mice reconstituted with CD4+ CD45RBhigh T cells (Jiang et al. 2002)
• H. hepaticus may alter gene expression profiles in the cecum (Myles et al. 2003)
Immunology
•H. hepaticus hepatitis is associated with expression of heat shock protein 70 in the
liver and with production of serum antibodies against this protein (Ward et al.
1996b)
• H. hepaticus hepatitis is associated with a Th1 cell-mediated immune response
(Whary et al. 1998)
• H. hepaticus and H. bilis increase MHC class II expression and proinflammatory
cytokine mRNA expression (skewed towards a Th1 phenotype) in the colons of immunodeficient mice with inflammatory bowel disease (Burich et al. 2001, Kullberg
et al. 2001, Tomczak et al. 2003)
• H. hepaticus induces IkB degradation and NF-kB activation in macrophages (Tomczak et al. 2003)
Interactions with other infectious agents
• H. hepaticus may modulate the pathogenesis of mouse hepatitis virus infection
(Compton et al. 2003)
Toxicology
• H. hepaticus produces a toxin with granulating cytotoxic activity in mouse liver
cells (Taylor et al. 1995) and a cytolethal distending toxin which causes cell distension, accumulation of filamentous actin, and G2/M cell cycle arrest in HeLa cells
(Young et al. 2000)
Oncology
• H. hepaticus may alter hepatocellular amd biliary epithelial apoptosis and proliferation indices (Ward et al. 1994a, Fox et al. 1996a, Nyska et al. 1997, Ihrig et al.
1999)
• H. hepaticus hepatitis is associated with increased oxidative DNA damage and
overexpression of specific cytochrome P450 isoforms (Sipowicz et al. 1997), epidermal growth factor, transforming growth factor-a, cyclin D1, cyclin-dependent kinase 4, and c-Myc in the liver (Ramljak et al. 1998)
• chronic H. hepaticus infection may increase the incidence of liver tumors (Ward et
al. 1994b, Fox et al. 1996a, Hailey et al. 1998) and promote the development and
malignancy of liver tumors initiated by chemical carcinogens (Diwan et al. 1997)
• H. hepaticus-driven inflammatory bowel disease may promote colon cancer (Erdmann et al. 2003)
• H. hepaticus can contaminate transplantable tumors (Goto et al. 2001)
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Clinical Microbiology 39, 3703-4
Goto K, Ohashi H, Takakura A, Itoh T (2000) Current status of Helicobacter contamination of laboratory mice, rats, gerbils, and house musk shrews in Japan. Current Microbiology 41, 161-6
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Ihrig M, Schrenzel MD, Fox JG (1999) Differential susceptibility to hepatic inflammation
and proliferation in AXB recombinant inbred mice chronically infected with Helicobacter
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Jiang H-Q, Kushnir N, Thurnheer MC, Bos NA, Cebra JJ (2002) Monoassociation of SCID
mice with Helicobacter muridarum, but not four other enterics, provokes IBD upon receipt
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Kullberg MC, Rothfuchs AG, Jankovic D, Caspar P, Wynn TA, Gorelick PL, Cheever A,
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Kullberg MC, Ward JM, Gorelick PL, Caspar P, Hieny S, Cheever A, Jankovic D, Sher A
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agents. Lab Animal 32(5), 44-51
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Myles MH, Livingston RS, Livingston BA, Criley JM, Franklin CL (2003) Analysis of gene
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Author: H. Meyer / M. Mähler
Mycoplasma pulmonis
Host species
• rat, mouse (rarely found in rabbits and guinea pigs)
Clinical disease and pathology
• commonly chronic respiratory infections in rats and mice
• acute bronchopneumonia in combination with other pneumotropic infections or
extrinsic factors as found in poorly managed conventional colonies by NH3, or nutritional deficencies
• sneezing and peculiar noises, inflammation of eyes and (middle-) ears
• genital tract infections with drop in fertility
Morbidity and mortality
• both low under optimal husbandry conditions
• high morbidity and mortality just in combination with other pneumotropic infections or extrinsic factors
Interference with research
(reviewed by Cassel et al., 1986):
Oncology
• Influence on carcinogenesis (increase or decrease tumor induction following exposure to carcinogen)
Physiology:
• Respiratory tract:
• Damage of airway epithelial and alveolar epithelial cells, mucus secretion, in severe cases bronchitis, bronchiectasis, emphysema and abscesses in the lungs.
• Genital tract:
• Negative influences on in vitro and in vivo fertilization, on fetal development and
drop in fertility.
• Suppression on interferon induction
• Chronic mycoplasmal infections interfere with gerontologic studies, nutrition, toxicology and behavioral research (Lindsay et al., 1971).
Immunology:
• Nonspecific mitogenic effect upon lymphocytes
• Since M. pulmonis and M. arthritidis can persist for months and years in many organs (also spleen) a diversity of effects on the immune system have been described.
Cassell et al. (1986) have postulated three general mechanisms: (i) delay or prevention of antigenic recognition, (ii) derangement of immune regulations, or (iii) evasion of effector mechanisms.
References
Cassell, G., H., I. K. Davis, J. W. Simecka, J. R. Lindsey, N. R. Cox, S. Ross, and M. Fallon.
1986. Mycoplasmal infections: disease pathogenesis, implications for biomedical research,
and control. In Viral and Mycoplasmal Infections of Laboratory Animals. Effects on Biomedical Research. Edited by Bhatt, P. N., R. O. Jacoby, H. C. Morse III, and A. E. New. Academic Press, Inc., Orlando, Florida.
Lindsey, J. R., H. J. Baker, R. G. Overcash, G. H. Cassell, and C. E. Hunt. Murine chronic
respiratory disease. Am. J. Path. 1971; 64:675-716.
Author: F. Homberger / V. Kraft
Citrobacter rodentium
(formerly C. freundii biotype 4280 and Citrobacter genomospecies 9)
•
C. rodentium and MPEC (mouse pathogenic E. coli) are synonymous (Luperchio 2000)
Host species:
•
laboratory mice
•
one report about an epidemic outbreak in a gerbil colony (de la Puente-Redondo, 1999)
•
one report of an outbreak in a guinea pig colony (Ocholi 1988)
Organotropism:
•
etiologic agent of transmissible murine colonic hyperplasia (TMCH)
•
large bowel (descending colon is most affected)
Clinical disease:
•
infection in most adult mice is subclinical and self-limiting (Barthold 1978)
•
suckling mice, adult animals of some inbred strains (Barthold 1977, Itoh 1988, Silverman
1979), Han:NMRI mice (Bieniek 1976) and transgenic lines (Maggio-Price 1998) are more
susceptible and demonstrate clinical signs
•
clinical signs are nonspecific and include ruffled coat, weight loss, depression, stunting,
perianal fecal staining, pasty dark feces and dehydration
•
variable incidence of rectal prolapse in mice of all ages is indicative of infection (Brennan
1965, and others)
•
mice that recover may be refractory to reinfection (Barthold 1980)
•
streptomycin in the drinking water may influence the severity of the disease (necrosis, colitis)
(Luperchio 2000)
•
age, host genetic background, diet and indigenous microbiota influence disease expression
(Luperchio 2001)
•
mucosal hyperplasia is more severe in outbred NIH Swiss mice as compared with C3H/HeJ,
C57BL/6J and DBA/2J mice (Barthold 1977)
•
moderate hyperplasia in C3H/HeJ mice (Barthold 1977)
•
least degree of hyperplasia in C57BL/6J and DBA/2J mice (Barthold 1977)
•
commercial diets effect the baseline colon morphology and presumably the epithelial cell
turnover rate – the dietary constituents responsible for this effect are unknown (Barthold 1977)
•
germfree CF1 and C3H mice are highly susceptible, germfree C57BL/6 and NC mice are
susceptible, and germfree BALB/c are resistant to infection (Itoh 1988)
•
-/-
-/-
CD4 or TCR-β mice develop polymicrobial sepsis and end-organ damage (abscesses) and
succumb during acute infection (Bry 2004)
Pathology:
•
colitis
•
hallmark pathologic lesion: colonic hyperplasia with limited inflammation and epithelial cell
hyperproliferation in the descending colon (Barthold 1978)
•
characterized by crypt elongation, increased mitotic activity, mucosal thickening, variable
mucosal inflammation, crypt abscesses, occasional erosions and ulcers, healing and goblet
cell hyperplasia (Barthold 1978, National Research Council 1991)
•
necrosis of the colonic mucosa and severe colitis most notably in suckling mice (Luperchio
2000)
•
grossly thickened and rigid distal colon, devoid of formed feces
•
cecum is often empty and contracted
•
with increasing severity of disease, the entire colon, and less frequently, the cecum and ileum
may be involved
•
animals of some inbred strains and transgenic lines develop lesions as severe as those seen
in suckling mice: neutrophil infiltration of mucosa and submucosa, mucosal erosions and
necrosis (Barthold 1978)
•
mucosal hyperplasia is dependent on the host immune response (Higgins 1999)
•
infection generates a predominately lymphocytic infiltrate, characterized by CD4 T cells
+
situated near the proliferative epithelial crypts (Higgins 1999)
•
innate immunity can mediate acute responses to infection, but T and/or B lymphocytes
mediate most of the tissue pathology and inflammation in the later stages of infection
(Vallance 2002)
•
bacteremia and extra-intestinal infection are not hallmarks of infection, though recovery of
bacteria from blood and liver and spleen has been reported (Luperchio 2001)
•
-/-
-/-
B cell-deficient (MuMT ) or B and T cell-deficient (recombinase-activating gene 2 ) mice
develop severe pathology in the colon and internal organs and deteriorate rapidly during acute
infection (Bry 2004)
•
inflammatory and crypt hyperplastic responses in RAG1
-/-
mice are transient and infection is
often fatal (Vallance 2002)
•
RAG1
-/-
mice respond to infection primarily with a granulocytic infiltration of the colonic
mucosa (Vallance 2002)
•
hyperplastic responses do not occur in interferon (IFN)-γ receptor-deficient mice (Higgins
1999)
•
depletion of IFN-γ prevents crypt hyperplasia (Artis 1999)
Morbidity and mortality:
•
little morbidity and mortality in most adult mice, while mortality or runting is seen in weaningage mice (Barthold 1978, Barthold 1977)
•
increased level of mortality accompanied by a high incidence of rectal prolapse in outbred
Swiss-Webster mouse (Ediger 1974)
•
high mortality in T-cell receptor αβ transgenic mice (Maggio-Price 1998)
•
wild-type mice clear the infection; T and/or B lymphocytes are required to clear the infection
(Vallance 2002)
•
only limited mortality in most inbred and outbred strains
•
severity of hyperplasia does not correlate with mortality: C3H/HeJ mice did not develop more
severe hyperplasia as compared to outbred Swiss-Webster mice, but C3H/HeJ mice exhibited
45% mortality while no mortality was observed in Swiss-Webster mice (Luperchio 2001)
•
+
C57BL/6 mice depleted of CD4 T cells are highly susceptible to infection and develop severe
colitis (Vallance 2003)
•
LPS-hyporesponsive C3H/HeJ mice experience more rapid and extensive bacterial
colonization than SCID mice – high bacterial load is associated with accelerated crypt
hyperplasia, mucosal ulceration and bleeding, together with very high mortality rates (Vallance
2003)
•
immunodeficient mice (mice lacking IL12, IFN-γ, TNF receptor or both T and B lymphocytes)
are more susceptible to infection than immunocompetent mice (Goncalves 2001, Simmons
2002, Vallance 2002, Vallance 2003) and infection is often fatal in former mice
Zoonotic potential:
•
none
Interference with research:
Physiology
•
experimental stress can evoke more severe disease in infected mice
•
increase in total cellular β-catenin accompanied by an increase in nuclear β-catenin
concentrations; elevated levels preceded crypt elongation (Sellin 2001)
•
increased transcription of EGR-1 with subsequent activation of the MEK/extracellular signalregulated kinases (de Grado 2001)
•
increase in production of keratinocyte growth factor, which induces cell proliferation (Higgins
1999; Bajaj-Elliott 1998)
Immunology
•
mice with deficiencies in cell-mediated immunity or mice lacking T and B cells are more
susceptible to infection with C. rodentium (MacDonald 2003)
•
colonic hyperproliferation is associated with cytokinetic alterations (Barthold 1979)
•
increase of IL-10 secretion and inhibition of IL-2 and IL-4 secretion by mitogen-stimulated
murine spleen cells (Malstrom 1998)
•
variable effect on IFN-γ secretion, whereas the effect of enteropathogenic Escherichia coli
lysates is inhibitory (Malstrom 1998)
•
suppression of lymphocyte activation in vitro (Klapproth 2000)
•
highly polarized Th 1 immune response, characterized by increased levels of IL-12, IFN-γ and
TNF-α mRNA (Higgins 1999)
•
infected IL-12p40
-/-
and IFN-γ
-/-
mice mount anti-Citrobacter serum and gut associated IgA
responses and strongly express inducible NO synthase (iNOS) in mucosal tissue, despite
diminished serum nitrite/nitrate levels (Simmons 2002)
•
up-regulated expression of the mouse β-defensins (mBD)-1 and mBD-3 in colonic tissue in
C57BL/6 mice; in contrast, only up-regulated expression of mBD-3 in IL-12- and IFN-γdeficient mice (Simmons 2002)
Oncology
•
C. rodentium-induced hyperplasia can alter chemical carcinogenesis in the large bowel
(Barthold, 1977, 1980)
•
hyperplastic state of the colon serves as a promoter for colon tumorigenesis (Barthold 1977)
•
transient hyperplastic state increases susceptibility to the carcinogenic effect of 1,2dimethylhydrazine (DMH) in NIH Swiss mice
•
DMH administration concomitant with hyperplasia reduces the latency period for early
neoplastic lesions, however hyperplasia has no effect on already established tumors
•
hyperplastic lesions may be confused with neoplasia because associated cytokinetic
alterations share several common features with those observed in neoplasia (Barthold, 1979;
Pullinger 1960)
•
increase in cellular concentrations of cyclin D1 and c-Myc (proteins maintaining proliferation
status)
References:
Artis, D., C. S. Potten, K. J. Else, F. D. Finkelman, and R. K. Grencis. 1999. Trichuris muris: host
intestinal epithelial cell hyperproliferation during chronic infection is regulated by interferon-gamma.
Exp. Parasitol. 92: 144-153.
Bajaj-Elliott M., R. Poulsom, S. L. Pender, N. C. Wathen, and T. T. MacDonald. 1998. Interactions
between stromal cell-derived keratinocyte growth factor and epithelial transforming growth factor in
immune-mediated crypt cell hyperplasia. J. Clin. Investig. 102: 1473-1480.
Baker D. G. 1998. Natural pathogens of laboratory mice, rats, and rabbits and their effects on
research. Clin. Microbiol. Rev. 11 (2): 231-266
Barthold, S. W. 1979. Autoradiographic cytokinetics of colonic mucosal hyperplasia in mice. Cancer
Res. 39:24-29.
Barthold, S. W. 1980. The microbiology of transmissible murine colonic hyperplasia. Lab. Anim. Sci.
30: 167-173.
Barthold, S. W. and D. Beck. 1980. Modification of early dimethylhydrazine carcinogenesis by colonic
mucosal hyperplasia. Cancer Res. 40:4451-4455.
Barthold, S. W., G. L. Coleman, P. N. Bhatt, G. W. Osbaliston and A. M. Jonas. 1976. The etiology of
transmissible murine colonic hyperplasia. Lab.Anim. Sci. 26:889-894.
Barthold, S. W., G. L. Coleman, R. O. Jacoby, E. M. Livstone and A. M. Jonas. 1978. Transmissible
murine colonic hyperplasia, Vet. Path. 15:223-36.
Barthold, S. W., G. W. Osbaldiston, and A. M. Jonas. 1977. Dietary, bacterial and host genetic
interactions in the pathogenesis of transmissible murine colonic hyperplasia. Lab. Anim. Sci. 27: 938945.
Barthold, S. W., and A. M. Jonas. 1977. Morphogenesis of early 1,2dimethylhydrazine-induced lesion
and latent reduction of colonic carcinogenesis in mice by variant of Citrobacter freundii. Cancer Res.
37:4352-4360.
Bieniek, H., and B. Tober-Meyer 1976. Zur Ätiologie der Colitis und des Prolapsus recti bei der Maus.
Z. Versuchstierk. 18: 337-348.
Brennan, P. C., T. E. Fritz, R. J. Flynn and C. M. Poole. 1965. Citrobacter freundii associated with
diarrhoea in laboratory mice. Lab. Anim. Care 15: 266-275.
Bry L., and M. B. Brenner. 2004. Critical role of T cell-dependent serum antibody, but not the gutassociated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an
attaching and effacing pathogen.J. Immunol. 172: 433-441.
De Grado M., C. M. Rosenberger, A. Gauthier, B. A. Vallance, and B. B. Finlay. 2001.
Enteropathogenic Escherichia coli infection induces expression of early growth response factor by
activating mitogen-activated protein kinase cascades in epithelial cells. Infect. Immun. 69: 6217-6224.
Ediger R. D., R. M. Kovatch, and M. M. Rabstein. 1974. Colitis in mice with a high incidence of rectal
prolapse. Lab. Anim. Sci. 24: 488-494
Goncalves, N. S., M. Ghaem-Maghami, G. Monteleone, G. Frankel, G. Dougan, D. J. Lewis, C. P.
Simmons, and T. T. MacDonald. 2001. Critical role for tumor necrosis factor alpha in controlling the
number of lumenal pathogenic bacteria and immunopathology in infectious colitis. Immun. 69: 66516659.
Higgins, L. M., G. Frankel, I. Connerton, N. S. Goncalves, G. Dougan, and T. T. MacDonald. 1999.
Role of bacterial intimin in colonic hyperplasia and inflammation. Science. 285: 588-591.
Higgins, L. M., G. Frankel, G. Douce, G. Dougan, and T. T. MacDonald. 1999. Citrobacter rodentium
infection in mice elicits a mucosal Th 1 cytokine response and lesions similar to those in murine
inflammatory bowel disease. Infect. Immun. 67: 3031-3039.
Itoh K., T. Matsui, K. Tsuji, T. Mitsuoka, and K. Ueda. 1988. Genetic control in the susceptibility of
germfree inbred mice to infection by Escherichia coli O115a,c:K(B). Infect. Immun. 56: 930-935.
Klapproth J. M. A., I. C. A. Scaletsky, B. P. McNamara, L. C. Lai, C. Malstrom, S. P. James, and M. S.
Donnenberg. 2000. A large toxin from pathogenic Escherichia coli strains that inhibits lymphocyte
activation. Infect. Immun. 68: 2148-2155.
Luperchio S. A., J. V. Newman, C. A. Dangler, M. D. Schrenzel, D. J. Brenner, A. G. Steigerwalt, and
D. B. Schauer. 2000. Citrobacter rodentium, the causative agent of transmissible murine colonic
hyperplasia, exhibits clonality: synonymy of C. rodentium and mouse pathogenic Escherichia coli. J.
Clin. Microbiol. 38: 4343-4350.
Luperchio S. A., and D. B. Schauer. 2001. Molecular pathogenesis of Citrobacter rodentium and
transmissible murine colonic hyperplasia. Microb. Infect. 3: 333-340.
MacDonald, T. T., G. Frankel, G. Dougan, N. S. Goncalves, and C. Simmons. 2003. Host defences to
Citrobacter rodentium. Int. J. Med. Microbiol. 293: 87-93.
Maggio-Price L., K. L. Nicholson, K. M. Kline, T. Birkebak, I. Suzuki, D. L. Wilson, D. Schauer, and P.
J. Fink. 1998. Diminished reproduction, failure to thrive, and altered immunologic function in a colony
of T-cell receptor transgenic mice: possible role of Citrobacter rodentium. Lab. Anim. Sci. 48: 145-155.
Malstrom C., and S. James. 1998. Inhibition of murine splenic and mucosal lymphocyte function by
enteric bacterial products. Infect. Immun. 66: 3120-3127.
National Research Council. 1991. Infectious diseases of mice and rats: a report of the Institute of
Laboratory Animal Resources Committee on Infectious Diseases of Mice and Rats. National Academy
Press, Washington D.C.
Ocholi R. A., J. C. Chima, E. M. I. Uche, and I. L. Oyetunde. 1988. An epizootic infection of Citrobacter
freundii in a guinea pig colony. Lab. Anim. 22: 335-336.
Pulliger, B. D. and S. Iversen. 1960. Mammary tumor incidence in relation to age and number of litters
in C3Hf and RIIIf mice. Br. J. Cancer 14:267-278.
Schauer, D. B., B. A. Zabel, I. F. Pedraza, C. M. O'Hara, A. G. Steigerwald and D. J. Brenner. 1995.
Genetic and biochemical characterization of Citrobacter rodentium sp. nov. J. Clin. Microbiol. 33:20642068.
Sellin J. H., S. Umar, J. Xiao, and A. P. Morris. 2001. Increased beta-catenin expression and nuclear
translocation accompany cellular hyperproliferation in vivo. Cancer Res. 61: 2899-2906.
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murine colonic hyperplasia in A/J mice. Lab. Anim. Sci. 29: 209-213.
Simmons, C. P., N. S. Goncalves, M. Ghaem-Maghami, M. Bajaj-Elliott, S. Clare, B. Neves, G.
Frnakel, G. Dougan, and T. T. MacDonald. 2002. Impaired resistance and enhanced pathology during
infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in
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Authors: P. Kirsch / H. Meyer
Corynebacterium kutscheri
Host species
• mouse, rat, (guinea pig, hamster)
Organotropism
• respiratory tract (other organs)
• middle ear
• superficial tissue
• generalization
Clinical disease and pathology
• inapparent in most strains of immunocompetent mice und rats
• abscesses of superficial tissue with microabscessation of various internal organs
• pneumonia in some strains of rats
Morbidity and mortality
• up to 100% of animals are infected
• 5-60% of susceptible strains show clinical signs (Amao, 1993)
• no age or sex prevalence are known
Zoonotic potential
• C.kutscheri was isolated from umbilical cord and other surface in an infant (Fitter,
1979)
Interference with research
Infection with this agent is usually subclinical in rats and mice and results in disease expressions only after severe immunosuppression, by exposure to experimental regimes,
dietary deficiencies, or concurrent infection with other agents.
Physiology
• Disease has been active in animals used in studies of dietary deficiency (Zucker,
1954), gamma irradiation (Schechmeister, 1953), cortisone administration (Takagaki, 1967), or by other infectious disease, for example infectious ectromelia
(Lawrence, 1957)
Immunology
• components of C. kutscheri may stimulate type -1 helper T cells to produce IL-2
and IFN-gamma and the enhance cytokine production could contribute to the nonspecific resistance induced by this bacterium (Kita, 1992)
Oncology
• a T- cell mitogen of C. kutscheri induced a tumorlytic factor in mice ( Kita, 1995)
References
Amao, H., T. Akimoto, K. W. Takahashi, M. Nakagawa and M. Saito. 1991. Isolation of Corynebacterium kutscheri from aged Syrian hamsters (Mesocricetus auratus). Lab. Anim.
Sci. 41:265-268.
Amao, H., Y. Komukai, M. Sugiyama, T. R. Saito, K. W. Takahashi and M. Saito. 1993. Difference in susceptibility of mice among vatious strains to oral infection with Corynebacterium kutscheri. Jikken Dobutsu 42:539-545.
Amao, H., T. Kanamoto, Y. Komukai, K. W. Takahashi, T. Sawada, M. Saito and M. Sugiyama. 1995. Pathogenicity of Corynebacterium kutscheri in the Syrian hamster. J. Vet. Med.
Sci. 57:715-719.
Amao, H., Y. Komukai, M. Sugiyama, K. W. Takahashi, T. Sawada and M. Saito. 1995. Natural habitats of Corynebacterium kutscheri in subclinically infected ICGN and DBA/2
strains of mice. Lab Anim Sci. 45:6-10.
Amao, H., Y. Komukai, T. Akimoto, M. Sugiyama, K. W. Takahashi, T. Sawada and M. Saito. 1995. Natural and subclinical Corynebacterium kutscheri infection in rats. Lab. Anim.
Sci. 45:11-14.
Antopol, W., H. Quittner and I. Saphira. 1959. "Spontaneous" infection after the administration of cortisone and ACTH. Am. J. Pathol. 29:599-600.
Barrow, P. A. 1981. Corynebacterium kutscheri infection in wild voles (Microtus agrestis).
Br. Vet. J. 137:67-70.
Brownstein, D. G., S. W. Barthold, R. L. Adams, G. A. Terwilliger and J. G. Aftomis. 1985.
Experimental Corynebacterium kutscheri infection in rats: bacteriology and serology. Lab.
Anim. Sci. 35:135-138.
Fauve, R. M., C. H. Pierce-Chase and R. Dubois. 1964. Corynebaczetium pseudotuberculosis in mice. II. Active of natural and experimantal latent infections. J. Exp. Med. 120:283304.
Fitter, W. F., D. J. de Sa and H. Richardson. 1979. Chorioamnionitis and funisisdis due to
Corynebacterium kutscheri. Arch. Dis. Child. 54:710-712.
Fox, J. G., C. M. Beaucage and J. C. Murphy. 1979. Corynebacterium kutscheri pneumonia
in rats on long term tobacco inhalation studies. Annual Session AALAS, abstract 104.
Fox, J. G., S. M. Niemi, J. Ackerman and J. C. Murphy. 1987. Comparison of methods to
diagnose an epizootic of Corynebacterium kutscheri pneumonia in rats. Lab. Anim. Sci.
37:72-75.
Hirst, R. G. and R. J. Olds. 1978. Corynebacterium kutscheri and its alleged avirulent variant in mice. J. Hyg. (Lond.) 80:349-356.
Hirst, R. G. and M. E. Wallace. 1976. Inherited resistance to Corynebacterium kutscheri in
mice. Infect. Immun. 14:475-482.
Kita, E., N. Matsui, M. Sawaki, K. Mikasa and N. Katsui. 1995. Murine tumorlytic factor,
immunologically distinct from tumor necrosis factor alpha and -beta, induced in the serum
of mice treated with a T-cell mitogen of Corynebacterium kutscheri. Immunol. Lett.
46:101-106.
Kita, E., N. Kamikaidou, D. Oku, A. Nakano, N. Katsui and S. Kashiba. 1992. Nonspecific
stimulation of host defense by Corynebacterium kutscheri. III. Enhanced cytokine induction by the active moiety of C. kutscheri. Nat. Immun. 11:46-55.
Lawrence, J. J. 1957. Infection of laboratory mice with Corynebacterium murium. Aust. J.
Sci. 20:147-150.
Miyamae, T. 1982. Corynebacterium kutscheri invasiveness of the gastrointestinal tract in
young mice. Jikken Dobutsu 31:189-194.
Schechmeister, I. L. and F. L. Alder. 1953. Activation of pseudotuberculosis in mice exposed to sublethal total body radiation. J. Inf. Dis. 92:228-239.
Suzuki, E., K. Mochida and M. Nakagawa. 1988. Naturally occurring subclinical Corynebacterium kutscheri infection in laboratory rats: strain and age related antibody response.
Lab. Anim. Sci. 38:42-45.
Takagaki, Y. M., M. Naiki and M. Ito. 1967. Checking of infections due to Corynebacterium
and Tyzzer' s organism among mouse breeding colonies by cortisone-injection. Exp. Anim.
16:12-19.
Weisbroth, S. H. and S. Scher. 1968. Corynebacterium kutscheri infection in the mouse. I.
Report of an outbreak, bacteriology, and pathology of spontaneous infections. Lab. Anim.
Care 18:451-458.
Weisbroth, S. H. and S. Scher. 1968. Corynebacterium kutscheri infection in the mouse. II.
Diagnostic serology. Lab. Anim. Care 18:459-468.
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Author: Herbert Meyer, University of Ulm, Germany
Clostridium piliforme
(former Bacillus piliformis)
Host species
• all laboratory animals, other mammals (Tyzzer, 1917; Fries, 1977)
• one case of human infection (Smith et al. 1996)
Properies
• spores are highly resistent to formaline
• relatively sensitive to heat and certain chemical disinfectants (Itoh et al. 1987)
Susceptibility
• depending on genetic factors of the host (Hansen et al. 1990; Waggie et al. 1981)
• antigenetic differences among isolates of bacteria (Biovin et al. 1993; Franklin et al.
1994)
Organotropism
• liver
• heart
Clinical disease and pathology
• Anorexia and diarrhea of different severity
• hypertrophy and inflammation of the ileum
• focal necrosis in the liver and/or heart possible (Fries, 1977)
• mesenteric lymphadenopathy
• brain lesions in experimentally infected Mystromys albicaudatus (Waggie et al.
1986)
Morbidity and mortality
• inapparent infection, high mortality possible (breeding colonies)
• susceptibility to infection seems to depend on genetic factors of the host (Hansen et
al.1990; Waggie et al. 1981)
• isolates of different origin show heterogenicity and host specificity (Franklin et al.
1994)
• different strains of Cl. piliforme are likely to exist (Biovin et al. 1993)
Interference with research
Infectiology
• lower susceptibility to experimental arthritis caused by Y. enterocolitica (Gripenberg et al. 1993)
Notice
• Clostridium piliforme is a obligate intracellular parasite forming spores. It does not
growing on cell-free media. Cultivation in cell lines and embryonated eggs is possible (Spencer et al.1990, Riley at al.1990)
• Diagnosis with IFA (Fries, 1977), ELISA and Western blot (Motzel et al. 1991), PCR
(Duncan et al.. 1993; Goto et Itoh, 1994)
References
Boivin, G. P., R. R. Hook, and L. K. Riley. 1993. Antigenetic diversity in flagellar epitops
among Bacillus piliformis isolates. J Med Microbiology 38:177-182.
Duncan, A. J., R. J. Carman, G. J. Olsen, and K. H. Wilson. 1993. Assignment of the agent
of Tyzzer's disease to Clostridium piliforme comb. nov. on the basis of 16S rRNA sequence
analysis. Int. J. Syst: Bacteriol. 43:314-318.
Franklin, C. L., S.L. Motzel, C. L. Besch-Williford, R. R. Hook Jr., and L.K. Riley. 1994.
Tyzzer's infection: Host specifity of Clostridium piliforme isolates. Lab. Anim Sci. 44:568572.
Fries, A. S. 1977. Studies on Tyzzer's disease: Application of Immunofluorescence for Detection of Bacillus piliformis and for Demonstration of Antibodies to it in Sera from Mice
and Rabbits. Lab. Anim. 11:69-74.
Goto, K., and T. Itoh. 1994. Detection of Bacillus piliformis by specific amplification of ribosomal sequences. Exp Anim. 43:389-394.
Gripenberg-Lerche, C., and P. Toivanen. 1993. Yersinia associated arthritis in SHR rats:
effect of the microbial status of the host. Ann Rheum Dis 52:223-228.
Hansen. A. K., O. Svendson, and K. E. Mollegard-Hansen. 1990. Epidemiological studies of
Bacillus piliformis infection and Tyzzer's disease in laboratory rats. Z Versuchtierk 33:163169.
Motzel, S. L., J. K. Meyer, L. K. Riley. 1991. Detection of Serum Antibodies to Bacillus piliformis in Mice and Rats Using an Enzyme-Linked-Immuonosorbent-Assay. Lab Amin Sci
41:26-30.
Riley, L. K., C. Besch-Williford, and K.S. Waggie. 1990. Protein and antigenetic heterogenicity among isolates of Bacillus piliformis. Infect. Immun. 58:1010-1016.
Smith, K., H. G. Skelton, E. J. Hilyard, T. Hadfield, R. S. Moeller, S. Tuur, C. Decker, K. F.
Wagner, and P. Angritt. 1996. Bacillus piliformis infection (Tyzzer's disease) in a patient
infected with HIV-1: confirmation with 16S ribosomal RNA sequence analysis. J. Am.
Acad. Dermatol. 34:343-348.
Spencer, T. H., J. R. Ganaway, and K. S. Waggie. 1990. Cultivation of Bacillus piliformis
(Tyzzer) in mouse fibroblasts (3T3 cells): Vet. Microbiol. 22:291-297.
Tyzzer, E. E. 1917. A Fatal Disease of the Japanese Waltzing Mouse Caused by a Spore-bearing Bacillus (Bacillus piliformis). J Med Res 37:307-338.
Waggie, K. S., C. T. Hansen, J. R. Ganaway, and T. S. Spencer. 1981. A Study of Mouse
Strain Susceptibility to Bacillus piliformis (Tyzzer's disease). The Association of B-Cell
Function and Resistence. Lab Anim Sci 31:139-142.
Waggie, K. S., L. P. Thornburg, and J. E. Wagner. 1986. Experimentally induced Tyzzer's
disease in the African white-tailed rat (Mystromys albicaudatus). Lab. Anim. Sci. 36:492495.
Bordetella bronchiseptica
Host species
• laboratory animals (Goodnow 1980)
• wide range of domestic and wild mammalian animals, birds, humans
Organotropism
• respiratory tract
Clinical disease
• many infected animals remain asymptomatic (Bemis 1992)
• clinical disease is most commonly associated with respiratory symptoms such as
sneezing, oculonasal discharge, coughing, and dyspnoe; signs of systemic disease
include pyrexia, anorexia, chorioretinitis, vomiting, and diarrhea (Goodnow 1980,
Harkness & Wagner 1995, Keil & Fenwick 1998, Speakman et al. 1999)
• pig: atrophic rhinitis with resultant twisting or shortening of the snout; most severe disease in combination with toxigenic Pasteurella multocida infection (Kamp &
Kimman 1988, Sakano et al. 1992)
• dog: infectious tracheobronchitis (kennel cough) (Goodnow 1980, Keil & Fenwick
1998)
• rabbit: snuffles; most infections become problematic only in association with
Pasteurella multocida infection (Deeb et al. 1990)
Pathology
• pig : rhinitis, atrophy of nasal turbinate bones, pneumonia (Goodnow 1980, Kamp
& Kimman 1988, Sakano et al. 1992); ultrastructural changes in the turbinates are
characterized by progressive degenerative changes in osteoblasts and osteocytes
(Fetter et al. 1975, Silveira et al. 1982)
• dog: rhinitis, sinusitis, tracheobronchitis, pneumonia (Goodnow 1980, Bemis 1992)
• cat : tracheitis, suppurative bronchopneumonia, lymphadenitis (Speakman et al.
1999)
• rabbit: serous to purulent rhinitis, catarrhal to purulent bronchopneumonia, pleuritis, hyperplasia of lymphoid tissues (Watson et al. 1972, Deeb et al. 1990, Glavits
& Magyar 1990, Harkness & Wagner 1995)
• guinea pig: serous to purulent otitis media, necrotizing tracheitis, suppurative necrotizing bronchopneumonia (Boot & Walfoort 1986, Trahan et al. 1987, Harkness
& Wagner 1995)
• rat: acute to subacute bronchopneumonia, atrophic rhinitis (Burek et al. 1972,
Kimman & Kamp 1986)
Morbidity and mortality
• differential host susceptibility: pigs, dogs, and guinea pigs are most susceptible;
rats, rabbits, and horses have moderate susceptibility; chickens, mice, and humans
are least susceptible (Goodnow 1980, Bemis 1992, Harkness & Wagner 1995)
• B. bronchiseptica infection prevalence may vary from 0 to 100% depending on the
population being tested; infections are generally higher in young animals, debiliated animals, and animals kept in close confinement
• variation in the pathogenicity of B. bronchiseptica isolates
• disease associated with B. bronchiseptica is frequently accompanied by infection
with other agents
• in general low mortality
Zoonotic relevance
• transmissible between species
• airborne and contact transmission
• infections in humans are often associated with an immunocompromised host (Woolfrey & Moody 1991)
Interference with research
Physiology
• lactic dehydrogenase activity and lactic acid and total protein concentrations were
higher, and alkaline phosphatase acitivity was lower in blood plasma of severely
affected pigs early in B. bronchiseptica infection compared with controls (Baetz et
al. 1974)
• neutral mucins are decreased in nasal mucosa of pigs infected with B. bronchiseptica (Perfumo et al. 1998)
• in dogs, B. bronchiseptica infection leads to bronchial hyperresponsiveness to histamine (Dixon et al. 1979, Richards 1983) and methacholine (Nishikata et al. 1989);
in guinea pigs, infection leads to hyperresponsiveness to histamine in the nasal
mucosa with increased vascular permeability and recruitment of nociceptive nerveparasympathetic reflexes (Gawin et al. 1998)
• B. bronchiseptica dermonecrotizing toxin (DNT) impairs bone formation (Horiguchi
et al. 1995a)
Cell biology
• adherence of B. bronchiseptica to ciliated respiratory epithelial cells (Yokomizo &
Shimizu 1979, Cotter et al. 1998) and induction of ciliostasis (Bemis & Wilson
1985)
• evidence for binding of B. bronchiseptica to sialyl glycoconjugates on swine nasal
mucosa (Ishikawa & Isayama 1987) and to glycosylated receptors on dendritic cells
(Guzman et al. 1994a)
• internalization and persistence of B. bronchiseptica in dendritic, epithelial, and
phagocytic cells (Guzman et al. 1994b, Schipper et al. 1994, Forde et al. 1998)
• B. bronchiseptica exerts a cytotoxic effect on various human cell lines (van den Akker 1997)
• in osteoblast-like MC3T3-E1 cells, B. bronchiseptica DNT induces a morphological
change, inhibits elevation of alkaline phosphatase activity, reduces accumulation of
type I collagen (Horiguchi et al. 1991), stimulates DNA synthesis (Horiguchi et al.
1993) and protein synthesis (Horiguchi et al. 1994), induces membrane organelle
proliferation and caveolae formation (Senda et al. 1997), and causes actin stress fiber formation and focal adhesions through the activation of the GTP-binding protein Rho (Horiguchi et al. 1995b, Horiguchi et al. 1997)
• in Swiss 3T3 fibroblasts, Bordetella bronchiseptica DNT induces p21rho-dependent
tyrosine phosphorylation of focal adhesion kinase and paxillin (Lacerda et al. 1997)
Immunology
• alveolar macrophages from rabbits colonized with B. bronchiseptica exhibit ultrastructural and functional changes (alteration of metabolic activities upon stimulation, decreases in cell adherence, phagocytic uptake, and bactericidal activity)
(Hoidal et al. 1978, Zeligs et al. 1986)
• neutrophils are critical to the early defense against B. bronchiseptica infection
(Harvill et al. 1999)
• B. bronchiseptica induces primarily a Th1-type T-cell response (Gueirard et al.
1996)
• serum concentrations of C-reactive protein are increased in dogs and monkeys infected with B. bronchiseptica (Yamamoto et al. 1994, Jinbo et al. 1999)
• B. bronchiseptica DNT suppresses antibody responses in mice (Horiguchi et al.
1992)
Interactions with other infectious agents
• B. bronchiseptica colonization may increase the severity of canine parainfluenza-2
virus in dogs (Wagener et al. 1984)
• B. bronchiseptica infection predisposes the nasal mucosa to colonization with
Pasteurella multocida in pigs (Chanter et al. 1989, Elias et al. 1992) and rabbits
(Deeb et al. 1990, Harkness & Wagner 1995) enhanced adherence of Pasteurella
multocida to porcine tracheal rings preinfected with Bordetella bronchiseptica (Dugal et al. 1992)
References
Baetz AL, Kemeny LJ, Graham CK (1974) Blood chemical changes in growing pigs exposed to aerosol of Bordetella bronchiseptica. American Journal of Veterinary Research 35,
451-3
Bemis DA (1992) Bordetella and Mycoplasma respiratory infections in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 22, 1173-86
Bemis DA, Wilson SA (1985) Influence of potential virulence determinants on Bordetella
bronchiseptica-induced ciliostasis. Infection and Immunity 50, 35-42
Boot R, Walvoort HC (1986) Otitis media in guineapigs: pathology and bacteriology. Laboratory Animals 20, 242-8
Burek JD, Jersey GC, Whitehair CK, Carter GR (1972) The pathology and pathogenesis of
Bordetella bronchiseptica and Pasteurella pneumotropica infection in conventional and
germfree rats. Laboratory Animal Science 22, 844-9
Chanter N, Magyar T, Rutter JM (1989) Interactions between Bordetella bronchiseptica
and toxigenic Pasteurella multocida in atrophic rhinitis of pigs. Research in Veterinary
Science 47, 48-53
Cotter PA, Yuk MH, Mattoo S, Akerley BJ, Boschwitz J, Relman DA, Miller JF (1998) Filamentous hemagglutinin of Bordetella bronchiseptica is required for efficient establishment
of tracheal colonization. Infection and Immunity 66, 5921-9
Deeb BJ, DiGiacomo RF, Bernard BL, Silbernagel SM (1990) Pasteurella multocida and
Bordetella bronchiseptica infections in rabbits. Journal of Clinical Microbiology 28, 70-5
Dixon M, Jackson DM, Richards IM (1979) The effect of a respiratory tract infection on
histamine induced changes in lung mechanics and irritant receptor discharge in dogs.
American Review of Respiratory Disease 120, 843-8
Dugal F, Belanger M, Jacques M (1992) Enhanced adherence of Pasteurella multocida to
porcine tracheal rings preinfected with Bordetella bronchiseptica. Canadian Journal of Veterinary Research 56, 260-4
Elias B, Albert M, Tuboly S, Rafai P (1992) Interaction between Bordetella bronchiseptica
and toxigenic Pasteurella multocida on the nasal mucosa of SPF piglets. Journal of Veterinary Medical Science 54, 1105-10
Fetter AW, Switzer WP, Capen CC (1975) Electron microscopic evaluation of bone cells in
pigs with experimentally induced Bordetella rhinitis (turbinate osteoporosis). American
Journal of Veterinary Research 36, 15-22
Forde CB, Parton R, Coote JG (1998) Bioluminescence as a reporter of intracellular survival of Bordetella bronchiseptica in murine phagocytes. Infection and Immunity 66, 3198207
Gawin AZ, Kaliner M, Baraniuk JN (1998) Enhancement of histamine-induced vascular
permeability in guinea pigs infected with Bordetella bronchiseptica. American Journal of
Rhinology 12, 143-7
Glavits R, Magyar T (1990) The pathology of experimental respiratory infection with
Pasteurella multocida and Bordetella bronchiseptica in rabbits. Acta Veterinaria Hungarica 38, 211-5
Goodnow RA (1980) Biology of Bordetella bronchiseptica. Microbiological Reviews 44, 72238
Gueirard P, Minoprio P, Guiso N (1996) Intranasal inoculation of Bordetella bronchiseptica
in mice induces long-lasting antibody and T-cell mediated immune responses. Scandinavian Journal of Immunology 43, 181-92
Guzman CA, Rohde M, Timmis KN (1994a) Mechanisms involved in uptake of Bordetella
bronchiseptica by mouse dendritic cells. Infection and Immunity 62, 5538-44
Guzman CA, Rohde M, Timmis KN (1994b) Invasion and intracellular survival of Bordetella bronchiseptica in mouse dendritic cells. Infection and Immunity 62, 5528-37
Harkness JE, Wagner JE (1995) Bordetella bronchiseptica infections. In: The Biology and
Medicine of Rabbits and Rodents. Baltimore: Williams & Wilkins, pp 182-5
Harvill ET, Cotter PA, Yuk MH, Miller JF (1999) Probing the function of Bordetella bronchiseptica adenylate cyclase toxin by manipulating host immunity. Infection and Immunity 67, 1493-500
Hoidal JR, Beall GD, Rasp FL, Holmes B, White JG, Repine JE (1978) Comparison of the
metabolism of alveolar macrophages from humans, rats, and rabbits: phorbol myristate
acetate. Journal of Laboratory and Clinical Medicine 92, 787-94
of the National Academy of Sciences of the United States of America 94, 11623-6
Horiguchi Y, Matsuda H, Koyama H, Nakai T, Kume K (1992) Bordetella bronchiseptica
dermonecrotizing toxin suppresses in vivo antibody responses in mice. FEMS Microbiology
Letters 69, 229-34
Horiguchi Y, Nakai T, Kume K (1991) Effects of Bordetella bronchiseptica dermonecrotic
toxin on the structure and function of osteoblastic clone MC3T3-E1 cells. Infection and Immunity 59, 1112-6
Horiguchi Y, Okada T, Sugimoto N, Morikawa Y, Katahira J, Matsuda M (1995a) Effects of
Bordetella bronchiseptica dermonecrotizing toxin on bone formation in calvaria of neonatal rats. FEMS Immunology and Medical Microbiology 12, 29-32
Horiguchi Y, Senda T, Sugimoto N, Katahira J, Matsuda M (1995b) Bordetella bronchiseptica dermonecrotizing toxin stimulates assembly of actin stress fibers and focal adhesions
by modifying the small GTP-binding protein rho. Journal of Cell Science 108, 3243-51
Horiguchi Y, Sugimoto N, Matsuda M (1993) Stimulation of DNA synthesis in osteoblastlike MC3T3-E1 cells by Bordetella bronchiseptica dermonecrotic toxin. Infection and Immunity 61, 3611-5
Horiguchi Y, Sugimoto N, Matsuda M (1994) Bordetella bronchiseptica dermonecrotizing
toxin stimulates protein synthesis in an osteoblastic clone, MC3T3-E1 cells. FEMS Microbiology Letters 120, 19-22
Ishikawa H, Isayama Y (1987) Evidence for sialyl glycoconjugates as receptors for Bordetella bronchiseptica on swine nasal mucosa. Infection and Immunity 55, 1607-9
Jinbo T, Ami Y, Suzaki Y, Kobune F, Ro S, Naiki M, Iguchi K, Yamamoto S (1999) Concentrations of C-reactive protein in normal monkeys (Macaca irus) and in monkeys inoculated
with Bordetella bronchiseptica R-5 and measles virus. Veterinary Research Communications 23, 265-74
Keil DJ, Fenwick B (1998) Role of Bordetella bronchiseptica in infectious tracheobronchitis in dogs. Journal of the American Veterinary Medical Association 212, 200-7
Kamp EM, Kimman TG (1988) Induction of nasal turbinate atrophy in germ-free pigs,
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Lacerda HM, Pullinger GD, Lax AJ, Rozengurt E (1997) Cytotoxic necrotizing factor 1
from Escherichia coli and dermonecrotic toxin from Bordetella bronchiseptica induce
p21rho-dependent tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss
3T3 cells. Journal of Biological Chemistry 272, 9587-96
Nishikata H, Kobayashi H, Sato H, Okada Y, Adachi M, Takahashi T, Soejima K, Hosono
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25, 459Woolfrey BF, Moody JA (1991) Human infections associated with Bordetella bronchiseptica. Clinical Microbiology Reviews 4, 243-55
Yamamoto S, Shida T, Honda M, Ashida Y, Rikihisa Y, Odakura M, Hayashi S, Nomura M,
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Author: M. Mähler
Oxyurina
(Syphacia obvelata, Syphacia muris, Aspiculuris tetraptera)
Host species:
• Syphacia obvleata: mainly mouse (also rat, hamster, gerbil, wild rodents)
• Syphacia muris: mainly rat (also mouse, hamster, gerbil, wild rodents)
• Aspiculuris tetraptera: mouse, rat (rarely), wild rodents
Organotropism:
• intestinal tract : Syphacia primarily caecum / rectum, Aspiculuris primarily colon
Life cycle:
Syphacia:
direct cycle which requires only 11-15 days. Gravid females deposit their eggs in the perianal
region. The eggs become infectious within 6 hours.
three possible infectious routes:
• direct: by ingestion of embryonated eggs from the perianal region
• indirect: by ingestion of food or water contaminated with embryonated eggs
• retroinfection: when eggs hatch in the perianal region and the larvae migrate back
into the colon by way of the anus ( Flynn, 1973)
Aspiculuris:
Direct cycle requires 23-25 days. Females lay their eggs in the colon and the eggs leave the
host on faecal pellets. The eggs become infectious after 6-7 days at room temperature.
Infection by ingestion of infectious eggs (Flynn, 1973)
Clinical disease:
• subclinical
• symptoms are: poor condition, rough hair coats, reduced growth rate, rectal prolaps
(Hoag, 1961; Harwell and Boyd, 1968; Jacobson and Reed, 1974)
• experimentally with S. muris infected animals grew slower than uninfected animals
(Wagner, 1988)
• infection with S. muris retards the growth of young mice and accelerate the development of their hepatic monooxygenase system (Mohn and Philipp, 1981)
no clinical signs in experimentally infected animals (Flynn, 1973; Wescott, 1982)
Pathology:
• the prevalence of pinworms in an infected rodent population depends on age, sex
and host immune status
• in enzootically infected colonies, weanlings develop the greatest parasite loads,
males are more heavily parasitizied than females
• Syphacia numbers diminish with increasing age of the host (Wescott, 1982)
• athymic (nu/nu) mice have increased susceptibility (Jacobson and Reed, 1974)
• Mastomys coucha is more susceptible than the BALB/c mouse (Higgins et al.,
1990)
• in rats the infestation rates of Syphacia muris were higher in the WKY strain than in
the SHR strain (Lübcke et al., 1992)
• increase in resistance to pinworm infection with advancing age of rats (Wagner,
1988)
• pinworms of laboratory rodents are generally not considered pathogens (Flynn,
1973, Wescott, 1982)
Morbidity and mortality:
none
Zoonotic potential:
• S. obvelata seems to occur in people, but it has no known health significance
(Flynn, 1973; Kellogg et al., 1982; Ross et al., 1980; Wescott, 1982)
Interference with research:
• infection with pinworms reduces the occurrence of adjuvant-induced arthritis (Pearson and Taylor, 1975)
• infection alters the humoral response to nonparasitic antigenetic stimuli. This indicate that infection might modulate the immune system (Sato et al., 1995)
• infection with S. obvelata induces a proliferation of T- and B- lymphocytes in spleen
and lymph nodes and occasional germinal center formation (Beattie et al., 1981)
• athymic mice infected with pinworms develop a lymphoproliferative disorder which
eventually leads to lymphoma (Beattie et al., 1980; Baird et al., 1982)
• animals infected with pinworms are not suitable for growth studies (Wagner, 1988)
• infection with S. obvelata in mice causes a significant reduction of activity in behavioral studies (McNair and Timmons, 1977)
• in rats, intestinal transport of water and electrolytes is significantly decreased due to
pinworm infection (Lübcke et al., 1992)
Notice:
• the eggs of pinworms survive for weeks in the animal room environment (Flynn,
1973; Klement et al., 1996)
References:
Baird, S. M., G. M. Beattie, A. Lannom, J. S. Lipsick, , and N. O. Kaplan. 1981. Induction of
lymphoma in antigenetically stimulated athymic mice. Cancer Research 42:198-202.
Beattie, G. M., S. M. Baird, J. S. Lipsick, R. A. Lannom, and N. O. Kaplan. 1981. Induction of
T- and B- lymphocyte responses in antgenitically stimulated athymic mice. Cancer Research
41:2322-2327.
Beattie, G.M., S. Baird, R. Lannom, S. Slimmer, F.C. Jensen, and N.O. Kaplan. 1980. Induction of lymphoma in athymic mice: a model for study of the human disease. Proc. Natl. Acad.
Sci. 77:4971-4974.
Higgins-Opitz, S. B., C. D. Dettman, C. E. Dingle, C. B. Anderson, and P. J. Becker. 1990. Intestinal parasites of conventionally maintained BALB/c mice and Mastomys coucha and the effects of a concomitant schistosome infection. Lab Anim. 24:246-252.
Hoag, W. G. 1961. Oxyuriasis in laboratory mouse colonies. Am. J. Vet. Res. 22:150-153.
Jacobson, R. H., and N. D. Reed. 1974. The thymus dependency of resistance to pinworm infection in mice. J. Parasitol. 60:976-979.
Kellogg, H. S., and J. E. Wagner. 1982. Experimental transmission of Syphacia obvelata
among mice, rats, hamsters, and gerbils. Lab. Anim. Sci. 32:500-501.
Klement, P., J. M. Augustine, K. H. Delaney, G. Klement, and J. I. Weitz. 1996. An oral ivermectin regimen that eradicates pinworms (Syphacia spp.) in laboratory rats and mice. Lab.
Anim. SCI. 46:286-290.
Lübcke R., F. A. R. Hutchenson and G. O. Barbezat. .1992. Impaired intestinal electrolyte
transport in rats infested with the common parasite Spyphacia muris. Dig Dis Sci 37:60-64
McNair, D. M. and E. H. Timmons. 1977. Effects of Aspiculuris tetraptera and Syphacia obvelata on exploratory behavior of an inbred mouse strain. Lab. Anim. SCI. 27:38-42.
Mohn, G. and E.M. Philipp. 1977. Effects of Syphacia obvelata on the microsomial monooygenase sytem in mouse liver. Lab. Anim. 15:89-95.
Pearson, D. J., and G. Taylor. 1975. The influence of the nematode Syphacia obvelata on adjuvant arthritis in rats. Immunology 29:391-396.
Ross, C. R., J. E. Wagner, S. R. Wightmen, and S. E. Dill. 1980. Experimental transmission of
Syphacia muris among rats, mice, hamsters and gerbils. Lab. Anim. Sci. 30:35-37.
Sato, Y., H. K. Ooi, N. Nonaka, Y. Oku, and M. Kamiya. 1995. Antibody production in Syphacia
obvelata infected mice. J. Parasitol. 81:559-562.
Wagner M. 1988. The effect of infection with the pinworm (Syphacia muris) on rat growth. Lab.
Anim. Sci. 38:476-478.
Wescott, R. B. 1982. Helminths, in: The Mouse in Biomedical Research Vol.II: Diseases. Foster H. L., J. D. Small, and J. E. Fox (eds). p 373-384. Academic press, New York.
Author: Brunhilde Illgen-Wilcke, Novartis, Switzerland
Mites
Host species:
• mouse, rat, hamster, guinea pig, rabbit, etc.
Organotropism:
• skin
Clinical disease:
• varies according to host strain, sex, age, individual differences in sensitivity and ectoparasite load (Csiza and McMartin, 1976; Dawson, et al., 1986)
• scruffiness, pruritus, hairloss, scratch wounds, ulcerative pyodermatitis
Morbidity and mortality:
• up to 100% of a colony affected
• morbidity: variable; mortality: low
Zoonotic relevance:
• some mites (e.g. Ornithonyssus bacoti) (Fox, 1982)
Interference with research:
Physiology
• Mycoptes musculinus reduces contact sensitivity to oxazolone in mice (Laltoo and
Kind, 1979)
Pathology
• Myobia musculi causes secondary amyloidosis (Galton, 1963; Weissbroth, 1982)
Immunology
• induce IgE response in mice (Laltoo et al., 1979) and rats (Gilabert et al., 1990; Inagaki et al., 1985)
• dust mites and dust mite parts in feed and bedding induce IgE and delayed-type hypersensitivity response in mice (Motegi et al., 1993; Nakano et al., 1989)
• induction of allergic reaction in mice (Weisbroth et al., 1976)
Infectiology
• dust mite proteases augment influenza virus replication in ferrets (Akaike, et al.,
1994)
• serve as vectors for other infectious diseases such as dematophytes (Hajsig and
Cuturic, 1969), cotton rat filariasis (Kershaw and Storey, 1976) and epidemic hemorrhagic fever virus (Zhang, 1987)
References:
Akaike, T., H. Maeda, K. Maruo, Y. Sakata, and K. Sato. 1994. Potentiation of infectivity and
pathogenesis of influenza A virus by a house dust mite protease. J. Infect. Dis. 170:1023-1026.
Csiza, C. K., and D. N. McMartin. 1976. Apparent acaridal dermatitis in a C57BL/6 Nya mouse
colony. Lab. Anim. Sci. 26:781-787.
Dawson, D. V., S. P. Whitmore, and J. F. Bresnahan. 1986. Genetic control of susceptibility to
mite-associated ulcerative dermatitis. Lab. Anim. Sci. 36:262-267.
Fox, J. G. 1982. Outbreak of tropical rat mite dermatitis in laboratory personnel. Arch. Dermatol. 118:676-678.
Galton, M. 1963. Myobic mange in the mouse leading to skin ulceration an amyloidosis. Am. J.
Pathol. 43:855-865.
Gilabert, A., J. Salgado, A. Franch, J. Queralt, and A. Torralba. 1990. Specific IgG and IgE responses to Dermatophagoides pteronyssinus in Sprague-Dawley rats. Rev. Esp. Fisiol.
46:353-357.
Hajsig, M., and S. Cuturic. 1969. Finding of the hair mite Myocoptes musculinus C. L. Koch in
a breed of white mice and its possible role in the spreading of dermophytosis. Mykosen
12:243-244.
Inagaki, N., N. Tsuruoka, S. Goto, T. Matsuyama, M. Daikoku, H. Nagai, and A. Koda. 1985.
Immunoglobulin E antibody production against house dust mite, Dermatophagoides farinae, in
mice. J. Pharmacobiodyn. 8:958-963.
Kershaw, W. E., and D. M. Storey. 1976. Host-parasite relations in cotton rat filariasis. I: The
quantitative transmission and subsequent development of Litomosoides carinii infections in
cotton rats and other laboratory animals. Ann Trop Med. Parasitol. 70:303-312.
Laltoo, H., and L. S. Kind. 1979. Reduction of contact sensitivity reactions to oxazolone in
mite-infested mice. Infect. Immun. 26:30-35.
Laltoo, H., T. Van Zoost, and L. S. Kind. 1979. IgE antibody response to mite antigens in mite
infested mice. Immunol. Commun. 8:1-9.
Motegi, Y., A. Morikawa, and T. Kuroume. 1993. Influence of environmental mite antigen on
anti-mite antibody production in mice. Int. Arch. Allergy Immunol. 102:81-86.
Nakano, Y., M. Yoshida, and T. Shibata. 1989. Strong delayed-type hypersensitivity induced
against house dust mite antigens in the mice. Int. Arch. Allergy Appl. Immunol. 88:434-438.
Weisbroth, S. H., S. Friedman, and S. Scher. 1976. The parasitic ecology of the rodent mite,
Myobia musculi. III. Lesions in certain host strains. Lab. Anim. Sci. 26:725-735.
Weisbroth S. H. 1982. Arthropods. p. 385-402. In H. J. Baker, J. R. Linsey and S. H. Weisbroth
(eds.), The laboratory rat, Vol. I. Academic Press, New York.
Zhang, Y. 1987. Transmission of epidemic hemorrhagic fever virus between mice and mites in
EHF endemic areas. Chung Hua Yu Fang I Hsueh Tsa Chih 21:325-327.
Author: Felix R. Homberger, University of Zurich, Switzerland
Spironucleus muris
formerly Hexamita muris - an intestinal flagellate
History:
Host species:
• Mouse (Meshorer 1969; Sebesteny 1969; Flatt 1978) rat, golden hamster (Wagner
et al 1974; Schagemann 1990), European hamster (Matthiesen et al. 1976, Hofmeister 1993), Mastomys coucha (Higgins-Opitz et al. 1990)
• There is evidence for a certain degree of host specificity: a mouse can obviously infect golden hamster and vice versa. A rat, however, can infect only another rat
(Kouchakji 1985, Schagemann et al. 1990)
• Inbred mouse strains differ in susceptibility (Wagner et al. 1974; Schagemann et al,
1990).
• It is suggested that the major histocompatibility complex haplotype may influence
susceptibility to S. muris (Baker et al. 1998). Minimal infectious dose is one fresh cyst
which appears bright in phase contrast optics (Stachan & Kunstyr 1983)
Organotropism:
• Intestine (trophozoites, i.e. active stage of the parasite); in the caecum and colon,
there are mainly cysts (Kunstyr 1978)
Clinical disease:
• Enlarged abdominal cavity (due to chronic enteritis), sometimes meteorism, diarrhoea and retarded growth in younger animals (Kunstyr 1978). Roughened hair coat,
hunched position, ìsticky stoolî (Wagner et al, 1974)
• Enhanced mortality, shortened life span in athymic mice (Boorman et al. 1973 a &
1973 b). Sporadic deaths by 4 weeks of age (Whitehouse et al. 1993)
Pathology:
• Enteritis, sometimes subepithelial edema, mononuclear inflammatory infiltrations in
the submucosa, desquamation of the epithelia, proliferation and thickening of the intestinal wall (Matthiesen et al. 1976). Accumulation of catarrhal fluid in the small intestine, sometimes hyperplasia of the epithelium (Wagner et al, 1974). Liquid, yellow/
green and often foamy contents of the small and large intestines (Whitehouse et al.
1993)
• Damages of microvilli, reduction of their height, increase in crypt depth (Brett & Cox
1982 a). Marked crypt hyperplasia, occasional crypt abscesses and variable degree of
villus atrophy (Whitehouse et al. 1993)
• Degeneration of enterocytes and even necrosis; in such areas, penetration of the intestinal barrier by individual trophozoites, exceptionally: invasion of plasma cells (Hofmeister 1993)
Morbidity and mortality:
• An opportunistic pathogen (feeding on intestinal bacteria) (Brugerolle et al. 1980)
• Some additional weakening / stressing factor(s), for instance athymic status (Boorman et al. 1973 a; Kunstyr et al. 1977), is / are necessary to elicit clinical disease
• Young animals are more sensitive (Sebesteny 1969), in older non-compromised animals a spontaneous recovery from the infection occurs (Kunstyr et al. 1977)
• Previously infected mice may show resistance to reinfection after recovery (Brett &
Cox 1982 a)
Zoonotic potential:
Interference with research:
• Increased mortality in cadmium exposed mice (Exon et al. 1975), shortened life
span in athymic mice (Boorman et al. 1973 a & 1973 b)
• Sometimes activation of the immune status (Ruitenberg & Kruyt 1975), sometimes
weakened immune response to some agents (Keast & Chesterman 1972), depression to mount an immune response to a thymus dependent antigen (Brett 1983)
• Impairment of the RNA-synthesis and of enzyme synthesis of macrophages
(Goodrum et al. (1984)
• Nonspecific activation of macrophages and, hence, enhanced elimination of tumour
cells (Keller 1973)
• Sometimes enhanced or impaired resistance to experimental infection with other
agents (Ruitenberg & Kruyt 1975, Higgins-Opitz et al. 1990)
• Decreased immune response to tetanus toxoid and pneumococci antigen in infected
mice (Ruitenberg & Kruyt 1975; Ruitenberg et al. 1975) but not in infected rats (Mullink et al. 1980). In contrast: enhanced resistance to experimental infection with Listeria monocytogenes (Ruitenberg et al. 1975)
• Concomitant infections with Babesia microti, Plasmodium berghei and P. yoelii decrease the output of trophozoites and cysts of S. muris (Brett & Cox 1982 b)
• Infected mice are unsuitable for immunologic studies (Sebesteny 1974)
• Increased sensitivity to X-irradiation (Myers 1973)
References:
Baker DG, Malineni S, Taylor HW (1998) Experimental infection in inbred mouse strains with
Spironucleus muris. Veterinary Parasitology 77,305-310
Boorman GA, Lina PHC, Zurcher C, Nieuwerkerk HTM (1973 a) Hexamita and Giardia as a
cause of mortality in congenitally thymus-less (nude) mice. Clinical and Experimental Immunology 15, 623-627
Boorman G.A, Van Hooft JIM, Van Der Waaij D, Van Noord MJ (1973 b) Synergistic role of intestinal flagellates and normal intestinal bacteria in post-weaning mortality of mice. Laboratory
Animal Science 23, 187-193
Brett SJ (1983) Immunodepression in Giardia muris and Spironucleus muris infections in mice.
Parasitology 87, 507-515
Brett SJ, Cox FE (1982 a) Immunological aspects of Giardia muris and Spironucleus muris infections in inbred and outbred strains of laboratory mice: a comparative study. Parasitology 85,
85-99
Brett SJ, Cox FE (1982 b) Interactions between the intestinal flagellates Giardia muris and Spironucleus muris and the blood parasites Babesia microti, Plasmodium yoelii and Plasmodium
berghei in mice. Parasitology 85, 101-110
Brugerolle G, Kunstyr I, Senaud J, Friedhoff KT (1980) Fine structure of trophozoites and cysts
of pathogenic diplomonad Spironucleus muris. Zeitschrift für Parasitenkunde / Parasitology
Research 62, 47-61
Exon JH, Patton NM, Koller LD (1975) Hexamitiasis in cadmium-exposed mice. Archives of
Environmental Health 30, 463-464
Flatt RE, Halvorsen JA, Kemp RL (1978) Hexamitiasis in a laboratory mouse colony. Laboratory Animal Science 28, 62-65
Goodrum KJ, Guzman GS, Lindsey JR, Silberman M , Spitznagel JK (1984) Peritoneal macrophages of pathogen-free rats but not of conventional rats secrete elastolytic activity. Journal of
Leukocyte Biology 36, 161-171
Higgins-Opitz SB, Dettman CD, Dingle CE, Anderson CB, Becker PJ (1990) Intestinal parasites of conventionally maintained BALAB/c mice and Mastomys coucha and the effects of a
concomitant schistosome infection. Laboratory Animals 24, 246-252
Hofmeister, K (1993) Spironukleose des Feldhamsters. Licht- und elektronenmikroskopische
Studie. Doctor Thesis/Dissertation, Tierärztliche Hochschule Hannover
Keast D, Chesterman FC (1972) Changes in macrophage metabolism in mice heavily infected
with Hexamita muris. Laboratory Animals 6, 33-39
Keller R (1973) Cytostatic elimination of syngeneic rat tumor cells in vitro by nonspecifically activated macrophages. Journal of Experimental Medicine 183, 625
Kouchakji GA (1985) Parasites of four wild rodent species in north-western Switzerland. PhD
Thesis, University of Basel
Kunstyr I (1978) Spironucleus muris und die Spironukleose thymusdefizienter Mäuse. PhD
Thesis, Medizinische Hochschule Hannover
Kunstyr I, Ammerpohl E, Meyer B (1977) Experimental spironucleosis (hexamitiasis) in the
nude mouse as a model for immunologic and pharmacologic studies. Laboratory Animal Science 24, 782-788
Matthiesen T, Kunstyr I, Tuch K (1976) Hexamita muris-Infektion bei Mäusen und Feldhamstern in einem Versuchstierbestand. Zeitschrift für Versuchstierkunde 18, 113-120
Meshorer A (1969) Hexamitiasis in laboratory mice. Laboratory Animal Care 19, 33-37. Laboratory Animals 14, 127-128
Mullink JWMA, Ruitenberg EJ, Kruizinga W (1980) Lack of effect of Spironucleus (Hexamita)
muris on the immune response to tetanus toxoid in the rat. Laboratory Animals 14, 127-128
Myers DD (1973) Sensitivity to X-irradiation of mice infected with Hexamita muris. 24th Annual
Meeting of the American Association of Laboratory Animal Science, Abstract No.22
Ruitenberg EJ, Kruyt BC (1975) Effect of intestinal flagellates on immune response of mice.
Parasitology 71, 30
Ruitenberg EJ, Kruyt BC, Kruizinga W, Buys J (1975) Effect of intestinal flagellates on immune
response in mice. Tropical and Geographical Medicine 27, 444
Schagemann G, Bohnet W, Kunstyr I, Friedhoff KT (1990) Host specificity of cloned Spironucleus muris in laboratory rodents. Laboratory Animals 24, 234-239
Sebesteny A (1969) Pathogenicity of intestinal flagellates in mice. Laboratory Animals 3, 71-77
Sebesteny A (1974) The transmission of intestinal flagellates between mice and rats. Laboratory Animals 8, 79-81
Stachan R, Kunstyr I (1983) Minimal infectious doses and prepatent periods in Giardia muris,
Spironucleus muris and Tritrichomonas muris. Zentralblatt für Bakteriologie, Mikrobiologie und
Hygiene A 256, 249-256
Wagner JE, Doyle RE, Ronald NC, Garrison RG, Schmitz JA (1974) Hexamitiasis in laboratory
mice, hamsters and rats. Laboratory Animal Science 24, 938-942
Whitehouse A, France MP, Pope SE, Lloyd JE, Ratcliffe RC (1993) Spironucleus muris in laboratory mice. Australian Veterinary Journal 70, 193
Author: I. Kunstyr