Download Department of Pathogen Molecular Biology

The London School of Hygiene & Tropical Medicine (LSHTM)
The mission of the LSHTM is to contribute to the
improvement of health worldwide through the pursuit of
excellence in research, postgraduate teaching and
advanced training in national and international public
health and tropical medicine, and through informing
policy and practice in these areas. The LSHTM was
rated second among UK institutions for research
excellent in the 2008 Research Assessment Exercise.
Leading researchers have backgrounds in public health
medicine, epidemiology, clinical medicine, infectious
diseases, chemotherapy, biochemistry, immunology,
genetics, molecular biology, entomology, statistics,
demography, health economics, public health
engineering, medical anthropology, health promotion,
and health policy.
The Faculty of Infectious and Tropical Diseases (ITD)
ITD encompasses all of the laboratory-based research
in the School as well as that on the clinical and public
health aspects of infectious and tropical diseases. The
range of disciplines represented in the Faculty is broad
and inter-disciplinary research is a feature of much of
our activity. The spectrum of diseases studied is wide
and there are major research groups with a focus on
malaria, tuberculosis, HIV/AIDS and other sexually
transmitted diseases, vaccine development and
evaluation, vector biology and disease control. The
Faculty is organized into four Departments comprising:
Disease Control, Clinical Research, Infections and
Immunology and Pathogen Molecular Biology. There is
close interaction between scientists in different
departments. The Faculty has strong overseas links,
which provide a basis for field studies and international
collaborations in developed and developing countries.
Department of Pathogen Molecular Biology
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Department of Pathogen Molecular
Biology
(PMBD)
In recent
years such
a mission has been significantly
Research in PMB focuses on the molecular biology and
genetics of pathogens and their hosts in the context of
enhanced by the availability of whole genome
sequences. The interpretation and exploitation of this
basic information is the platform for numerous new
improving the understanding and control of infectious
avenues of research on pathogenesis, epidemiology
diseases. Aspects of pathogen biology of interest
and the evolution of virulence.
include: (i) determining the mechanisms of infection of
globally important viral, bacterial and parasitic
The genome resource facility, bioinformatic suite and
pathogens, (ii) studying immune evasion mechanisms
of particular disease agents, (iii) deciphering the genetic
protein expression laboratory have greatly expedited
genome data mining, population genetics, mathematical
diversity of pathogens in natural populations, (iv)
modeling, phylogenetic and microarray analyses. One
exploiting parasitic, bacterial and viral pathogens as
example of the application of this technology has been
model biological systems and (v) developing practical
the development of “comparative phylogenomics” for
applications including improved diagnostics,
the whole genome comparison of pathogens coupled
antimicrobials and vaccines. PMB currently
with Bayesian-based algorithms to model phylogeny.
investigates, amongst others, malaria (Plasmodium
This method has identified previously hidden population
spp), Chagas disease (Trypanosoma cruzi), African
structures and has expedited the identification of novel
sleeping sickness (Trypanosoma brucei), amoebic
virulence factors and has now been applied to several
dysentery (Entamoeba), the Leishmania species,
pathogens. Other recent research projects include a
bacterial food borne pathogens (Campylobacter jejuni
project to optimize the expression of multiprotein
and Yersinia enterocolitica), gastric ulcers/cancer
complexes using the baculovirus system. This project
(Helicobacter pylori), pseudomembranous colitis
will have broad applicability to a range of pathogens,
(Clostridium difficile), plague (Yersinia pestis), paddy
and will support the current international lead the
field melioidosis (Burkholderia pseudomallei),
tuberculosis (Mycobacterium tuberculosis), pneumonia
(Streptococcus pneumoniae), bluetongue viral disease
Department has in the area of safe multiprotein
particulate vaccines against viral diseases. In the longer
term out research will help to translate the research
of livestock, Herpesviridae, and the enteric rotavirus
lead that we have in pathogen genomics into practical
that cause significant diarrhoeal disease in infants
applications and will facilitate research on the structural
developing countries.
analysis of virulence determinants and the development
of vaccines and antimicrobial agents.
The long-term aim of PMB research is to gain a fully
rounded understanding of the complex and dynamic
More details of PMB can be found on
ways by which pathogens modulate virulence and
http://www.lshtm.ac.uk/pmbu/
interact with the human/animal host. Such a holistic
approach will vastly increase the scope for the rational
design of long-term intervention strategies to reduce the
burden of infectious diseases.
Department of Pathogen Molecular Biology
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PMBD Research Staff
Brendan Wren, Head of PMBD and Professor of Microbial Pathogenesis
Professor Wren joined
Champion, O.L., Gaunt, M.W., Gundogdu, O., Elmi,
the School with his
A., Witney, A.A., Hinds, J., Dorrell, N., Wren, B.W.
research team in July
Comparative phylogenomics of the food-borne
1999. His research
pathogen Campylobacter jejuni reveals genetic
interests include
markers predictive of infection source. PNAS, 2005;
determining the
102(44):16043-8.
genetic basis by which bacterial pathogens cause
disease. Research on individual pathogens include;
Pallen, M.J., Wren, B.W. Bacterial pathogenomics
Clostridium difficile, Campylobacter jejuni, Helicobacter
Nature, 2007; 449(7164):835-842.
pylori, Bukrholderia pseudomallei, Streptococcus
pneumonia and the enteropathogenic Yersinia. The
He M et al. Evolutionary dynamics of Clostridium
research group currently exploits a range of post
difficile over short and long-time scales. PNAS
genome research strategies to gain a comprehensive
2010; 107 (16):7527-32.
understanding of how these pathogens function, how
they evolve and how they interact with their respective
hosts.
Circular representation of the plague genome
Current research focuses on:
1. Glycosylation in bacterial pathogens and their
application in glycoengineering and novel vaccine
design
2. Comparative phylogenomics and the evolution of
bacterial virulence.
3. Systems biology of host pathogen interactions.
____________________________________________
Selected publications
Wacker, M., et al. N-linked glycosylation in
Campylobacter jejuni and its functional transfer into
E-coli. Science, 2002; 298(5599):1790-1793.
Department of Pathogen Molecular Biology
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John Kelly, Professor of Molecular Biology
The parasitic protozoa
Selected publications
Trypanosoma cruzi and
Trypanosoma brucei are
Wilkinson, S.R., Taylor, M.C., Horn, D., Kelly, J.M.,
responsible for two major tropical
Cheeseman, I. A mechanism for cross-resistance to
infections, Chagas disease and
nifurtimox and benznidazole in trypanosomes.
African trypanosomiasis,
PNAS, 2008; 105(13):5022-7.
respectively. These diseases
Obado, S.O., Bot, C., Nilsson, D., Andersson, B.,
represent a major public health
problem in regions of the world least able to deal with
Kelly, J.M. Repetitive DNA is associated with
the associated economic burden. Advances by
centromeric domains in Trypanosoma brucei but not
ourselves, and others have led to the development of a
Trypanosoma cruzi. Genome Biol, 2007; 8(3):R37
wide range of genetic tools that can be used to address
fundamental biological questions associated with these
Kelly, J.M., McRobert, L., Baker, D.A. Evidence on
important pathogens. In addition, the recent completion
the chromosomal location of centromeric DNA in
of the trypanosomatid genome projects, together with
Plasmodium falciparum from etoposide-mediated
major advances in imaging technology, is providing a
topoisomerase-II cleavage. PNAS, 2006;
research framework where rapid progress can be
103(17):6706-11.
expected. We are exploiting these new approaches and
opportunities to gain greater understanding of the
Wilkinson, S.R., Prathalingam, S.R., Taylor, M.C.,
mechanisms of drug action and resistance, disease
Horn, D., Kelly, J.M. Vitamin C biosynthesis in
pathogenesis and genome inheritance. In collaboration
trypanosomes: A role for the glycosome. PNAS,
with biologists, biochemists and organic chemists, we
2005; 102:11645-11650
have validated a number of parasite drug targets and
identified several lead compounds that show promise in
terms of therapeutic development. This multidisciplinary
approach, which brings together of both academic and
industrial partners, is now widely seen as the way
ahead to provide better treatments for these previously
„Neglected Diseases‟.
Trypanosoma cruzi, expressing green and red fluorescent protein. The
ability to genetically modify parasites in this way has contributed
greatly to advances in cell and molecular biology, with multiple
downstream applications to areas such as drug development
Department of Pathogen Molecular Biology
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Michael Miles, Professor of Protozoology
Professor Mile‟s research is primarily focused on
Selected publications
Trypanosoma cruzi, the agent of Chagas disease
(South American trypanosomiasis) and on Leishmania
Gaunt, M. W., Yeo, M., Frame, I. A., Stothard, J.
species, the agents of visceral (VL) and mucocutaneous
R., Carrasco, H. J., Taylor, M. C., Mena, S. S.,
leishmaniasis (MCL), encompassing fundamental
Veazey, P., Miles, G. A., Acosta, N., de Arias, A.
laboratory research and fieldwork in endemic areas.
R., Miles, M. A. Mechanism of genetic exchange
Principal research interests are the presence,
in American trypanosomes Nature, 2003;
importance and mechanisms of genetic exchange in
421(6926):936-9
experimental and natural populations of these
organisms, and the molecular epidemiology of Chagas
Lukes, J., Mauricio, I.L., Schönian, G., Dujardin,
disease and the leishmaniases in the context of
J.C., Soteriadou, K., Dedet, J.P., Kuhls, K.,
improvement of control strategies. Other interests are
Tintaya, K.W., Jirk, M., Chocholová, E.,
comparative genomics, diagnostics development, the
Haralambous, C., Pratlong, F., Oborník, M.,
ecology and population genetics of triatomine bugs, the
Horák, A., Ayala, F.J., Miles, M.A. Evolutionary
ecology and behaviour of South American mammals,
and geographical history of the Leishmania
and the control of African trypanosomiasis. Recent
donovani complex with a revision of current
achievements of the research group include the first
taxonomy. PNAS, 2007; 104(22):9375-80
experimental proof of genetic exchange in T. cruzi;
demonstration that sylvatic Rhodnius prolixus does
Llewellyn, M.S., Miles, M.A., Carrasco, H.J.,
invades houses in Venezuela, and several detailed
Lewis, M.D., Yeo, M., Vargas, J., Torrico, F.,
population genetics studies of natural populations using
Diosque, P., Valente, V., Valente, S.A., Gaunt,
multilocus sequence typing (MLST) and microsatellite
M.W. Genome-scale multilocus microsatellite
analysis (MLMT). Coordinator, of the European/Latin
typing of Trypanosoma cruzi discrete typing unit
American FP6 network (LeishEpiNetSA), 12 partners, to
I reveals phylogeographic structure and specific
2010 - Coordinator (assisted by Martin Llewellyn), of the
genotypes linked to human infection. PLoS
European/Latin American FP7 network (ChagasEpiNet),
Pathog, 2009; 5(5):e1000410
15 partners, to 2011.
Miles, M.A., Llewellyn, M.S., Lewis, M.D., Yeo,
M., Baleela, R., Fitzpatrick, S., Gaunt, M.W.,
Mauricio, I.L. The molecular epidemiology and
phylogeography of Trypanosoma cruzi and
parallel research on Leishmania: looking back
and to the future. Parasitology, 2009; :1-20
Department of Pathogen Molecular Biology
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Polly Roy, Professor of Selected
Virology publications
Professor Roy joined the School
Roy, P., Zhang, X., Boyce, M., Bhattacharya, B.,
in March 2001 as Professor of
Schein, S. and Zhou, H. (2010). Sialic acid binding
Virology working in the field of
domains and amphipathic helices in coat proteins of
double-stranded RNA viruses.
bluetongue virus. PNAS. 107: 6292–6297.
Her group has made novel and
substantial contributions to the
Boyce, M., Celma, C., Roy, P. (2008). Development
medical and veterinary fields,
of Reverse Genetics Systems for Bluetongue Virus:
particularly through their studies
of multi-shelled viruses of serious pathological and
Recovery of Infectious Virus from Synthetic RNA
Transcripts. J. Virol. 82: 8339-48
economic impact. Professor Roy‟s most significant
contribution has been the provision of the first complete
molecular description of a distinct group of insect-borne
viruses, Orbiviruses, particularly Bluetongue virus; the
understanding of which – gained through a combination
of virology, molecular and structural studies – has been
instrumental in paving the way for improved diagnosis,
new vaccines and structure-based drug design.
Professor Roy‟s most recent research has continued to
Sutton, G., Grimes, J.M., Stuart, D.I., Roy, P.
(2007). Bluetongue virus VP4 is an RNA-capping
assembly line. Nat Struct Mol Biol. 14: 449-51
Forzan, M., Wirblich, C., Roy, P. (2004). A capsid
protein of nonenveloped Bluetongue virus exhibits
membrane fusion activity. PNAS. 101: 2100-5
centre on the basic understanding of each stage of the
viral life cycle as well as the diverse tropism of these
insect-transmitted viruses. Recently, the Roy group
pioneered the first reverse genetics system for BTV (the
synthesis of infectious virus solely from synthetic
genes). Such directed virus genetic manipulation opens
a new window of opportunity to understanding how the
virus invades a host to cause disease and will benefit
the development of new control and therapy regimens in
the longer term.
Department of Pathogen Molecular Biology
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David Conway, Professor of Biology
Department of Pathogen Molecular Biology
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Dr David Baker, Reader in Parasite Molecular Biology
David Baker‟s research group
Selected publications
uses biochemical and genetic
approaches to study the cyclic
L McRobert, C J Taylor, W Deng, Q L Fivelman, R
nucleotide signal transduction
M Cummings, S D Polley, O Billker and D A Baker
pathways of malaria parasites.
(2008) Gametogenesis in malaria parasites is
The cyclic nucleotides cAMP
mediated by the cGMP-dependent protein kinase.
and cGMP perform a spectrum
PLoS Biology 6, e139.
of cellular functions in diverse organisms. Earlier work
from other laboratories suggested that both of these
Moon, R.W., Taylor, C.J., Bex, C., Schepers, R.,
second messenger molecules may play roles in malaria
Goulding, D., Janse, C.J., Waters, A.P., Baker, D.A.,
parasite differentiation. Our studies have focused on the
Billker, O. (2009) A cyclic GMP signalling module
cyclase enzymes that synthesise cyclic nucleotides, the
that regulates gliding motility in a malaria parasite.
phosphodiesterases that degrade them, but also on the
PLoS Pathogens 5, e1000599.
protein kinase that is activated by cGMP (PKG). We
have found that in Plasmodium falciparum cGMP and
Taylor, H.M., McRobert, L., Grainger, M., Sicard, A.,
PKG play an essential role in triggering the formation
Dluzewski, A.R., Hopp, C.S., Holder, A.A., Baker,
(gametogenesis) of mature sexual parasite forms which
D.A. (2010) The malaria parasite cGMP-dependent
are required to transmit disease to the mosquito vector
protein kinase plays a central role in blood stage
[1]. We also showed that this pathway is important for
schizogony. Eukaryotic Cell 9, 37-45.
the development of the ookinete form of P. berghei
within the mosquito [2]. It is now becoming clear that
Dvorin, J.D., Martyn, D.C., Patel, S.D., Grimley,
cGMP signalling and the PKG enzyme are vital for
J.S., Collins, C.R., Hopp, C.S., Bright, A.T.,
multiple parasite stages, because using specific PKG
Westernberger, S., Winzeler, E., Blackman, M.J.,
inhibitors in conjunction with inhibitor-insensitive
Baker, D.A., Wandless, T.J., Duraisingh, M.T.
transgenic parasites we have demonstrated that
(2010) A plant-like kinase in Plasmodium falciparum
asexual blood stage schizogony cannot progress if this
regulates parasite egress from erythrocytes.
kinase is blocked [3]. Recently, with others we have
Science 14; 328(5980):910-2.
shown that PKG functions upstream of a protease
cascade and a calcium- dependent protein kinase
(CDPK5) that are also required for asexual blood stage
schizont rupture and merozoite egress [4]. Cyclic
nucleotide signalling pathways could be exploited in the
development of novel antimalarial drugs.
Department of Pathogen Molecular Biology
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Dr Graham Clark, Reader in Molecular Parasitology
The research falls into two
categories: 1. genetic diversity
Selected publications
and evolution of gut protozoan
parasites, and 2. evolution of
Loftus, B. et al., 2005 The genome of the protist
mitochondria in anaerobic
parasite Entamoeba histolytica. Nature 433: 865-
eukaryotes. The main organisms
868.
studied are Entamoeba
histolytica, the agent of amoebic
dysentery and amoebic liver abscesses, and
Ali, I.K.M., Mondal, U., Roy, S., Haque, R., Petri Jr.,
W.A., Clark, C.G. 2007 Evidence for a link between
Blastocystis, an organism of uncertain pathogenicity. In
Entamoeba, recent unpublished work has focused on
parasite genotype and outcome of infection with
Entamoeba histolytica. J. Clin. Microbiol. 45: 285-
genome re-sequencing as a way to build on earlier
289
results that indicated a parasite genetic component
linked to the outcome of infection with the parasite -
Stechmann, A., Hamblin, K., Pérez-Brocal, V.,
people who develop disease are infected with a different
range of genotypes from those who remain
Gaston, D., Richmond, G.S., van der Giezen, M.,
Clark, C.G. Roger, A.J. 2008 Organelles in
asymptomatic. The work on Blastocystis is focused on:
1. investigating whether any of the genetic subtypes in
Blastocystis that blur the distinction between
mitochondria and hydrogenosomes. Curr. Biol. 18:
the organism are linked to the symptoms found in some
580-5
individuals, and 2. sequencing its mitochondrial and
nuclear genomes in an attempt to understand the
Stensvold, C.R., Alfellani, M.A., Nørskov-Lauritsen,
function of the mitochondrion-like organelle in this
S., Prip, K., Victory, E.L., Maddox, C., Nielsen, H.V.,
strictly anaerobic organism. The latter studies are also
Clark, C.G. 2009 Subtype distribution of Blastocystis
using comparisons with a related organism,
isolates from synanthropic and zoo animals and
Proteromonas. The former (unpublished) has shown
identification of a new Blastocystis sp. subtype. Int.
that the one subtype is much more common in people
J. Parasitol. 39: 473-479
with symptoms, suggesting that Blastocystis may
indeed be responsible for disease in at least some
cases.
Department of Pathogen Molecular Biology
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Dr Ursula A. Gompels, Reader in Selected
Molecularpublications
Virology
Dr Gompels research is on human herpesviruses,
Bates, M., Monze, M., Bima, H., Kapambwe, M.,
currently focused on the betaherpesvirus subgroup
Kasolo, F.C., Gompels, U.A.; CIGNIS study group.
which includes human herpesvirus 6 (variants HHV-6A
High human cytomegalovirus loads and diverse
and HHV-6B) and human cytomegalovirus (HCMV).
linked variable genotypes in both HIV-1 infected and
These viruses can be significant paediatric pathogens
exposed, but uninfected, children in Africa.
and are major opportunistic infections in immune-
Virology.2008 ; 382:28-36.
suppressed populations, as HIV/AIDS and
transplantation patients, where they cause both
Catusse, J., Spinks, J., Mattick, C., Dyer, A., Laing,
morbidity and mortality. HHV-6, particularly HHV-6A, is
an emergent pathogen with links to multiple sclerosis
K., Fitzsimons, C., Smit, M.J., Gompels, U.A.
Immunomodulation by herpesvirus U51A chemokine
and other neuro-inflammatory disease.
receptor via CCL5 and FOG-2 down-regulation plus
Betaherpesviruses cause lifelong latent infections
XCR1 and CCR7 mimicry in human leukocytes. Eur
adapted to persist in cells of our immune system, and
J Immunol. 2008; 38:763-77.
can reactivate to cause disease. These adaptations
provide a unique immunological toolbox to devise novel
Catusse, J., Parry, C.M., Dewin, D.R., Gompels,
immune-based medicines.
U.A. Inhibition of HIV-1 infection by viral chemokine
U83A via high-affinity CCR5 interactions that block
Work is multidisciplinary with topics in infection and
immune modulation with implications for vaccine studies
and paediatric HIV/AIDS: i) genomic variation and viral
load in relation to micronutrients and paediatric disease
in maternally HIV exposed infants, in collaboration with
LSHTM EPH and the University Teaching Hospital in
human chemokine-induced leukocyte chemotaxis
and receptor internalization. Blood. 2007, 109:36339.
Dewin, D.R., Catusse, J., Gompels, U.A.
Identification and characterization of U83A viral
Zambia, ii) studies on molecular mechanisms of virus
chemokine, a broad and potent beta-chemokine
entry mediated by cell fusion and iii) characterisation of
virus mimics of inflammatory mediators, chemokine and
chemokine receptors, as major components of immune
agonist for human CCRs with unique selectivity and
inhibition by spliced isoform. J Immunol. 2006
176:544-56.
modulation. Recent studies identified viral chemokine
agonist and antagonists with HIV-1 inhibitory properties
plus applications for both vaccines and inflammatory
disease inhibition.
Department of Pathogen Molecular Biology
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Dr David Horn, Reader in Molecular Biology and Head of African trypanosome laboratory
Trypanosomatids are protozoan
Selected publications
parasites that cause a variety of
devastating human and animal
Kawahara, T., Siegel, T.N., Ingram, A.K., Alsford,
diseases, including African
S., Cross, G.A., Horn, D. Two essential MYST-
trypanosomaiasis, Chagas
family proteins display distinct roles in histone
disease and leishmaniasis. The
H4K10 acetylation and telomeric silencing in
work is funded by The Wellcome
trypanosomes. Mol Microbiol, 2008; 69(4):1054-68
Trust and focuses on
understanding gene expression control in Trypanosoma
Glover, L., McCulloch, R., Horn, D. Sequence
brucei, more specifically, molecular mechanisms
homology and microhomology dominate
underlying antigenic variation and host immune evasion.
chromosomal double-strand break repair in African
This involves projects on monoallelic transcription
trypanosomes. Nucleic Acids Res, 2008;
control, DNA recombination and repair and telomere
36(8):2608-18
biology. The team has also pioneered technology
Alsford, S., Kawahara, T., Isamah, C., Horn, D. A
development to facilitate exploitation of genome
sequence data and is currently using RNA interference
sirtuin in the African trypanosome is involved in both
DNA repair and telomeric gene silencing but is not
libraries to identify and to study targets and drug
required for antigenic variation. Mol Microbiol, 2007;
resistance mechanisms. The work incorporates a
number of collaborative projects across the UK, Europe,
63(3):724-36
USA and South Africa. The laboratory provides
Glover, L., Horn, D. Repression of polymerase I-
research laboratory training at various levels with two
current Ph.D. students and a Masters student working in
mediated gene expression at Trypanosoma brucei
telomeres. EMBO Rep, 2006; 7(1):93-9
the laboratory. Dr Horn is currently the Departmental
(PMB) Research Degree Coordinator and will organise
the M.Sc. Advanced Training in Molecular Biology
module from 2010.
Department of Pathogen Molecular Biology
Page 11 of 18
Dr Taane Clark, Reader in Genetic Epidemiology and Statistics
Taane joined the LSHTM in
early 2010, after holding senior
Selected publications
statistician appointments at the
Wellcome Trust Sanger Institute
Jallow, M. et al.,. Genome-wide and fine-resolution
(WTSI) and Wellcome Trust
association analysis of malaria in West Africa
Centre for Human Genetics
Nature Genetics, 2009; 41:657-665
(Oxford), where he focused on
the genomic epidemiology of malaria. His main research
MalariaGEN Consortium (TG Clark = Statistics
interests include the design and analysis of large-scale
lead). A global network for genomic epidemiology
association studies of infectious diseases in humans
of malaria. Nature. 2008; 456:732-7.
and the investigation of genetic variation in pathogen
populations (e.g. Leishmania, Mycobacterium TB (Mtb),
Clark, T.G., Fry, A.E., Auburn, S., Campino, S.,
Plasmodium) using high-throughput sequencing
Diakite, M., Green, A., Richardson, A., Teo, Y.Y.,
technologies. This research includes developing new
Small, K., Wilson, J., Jallow, M., Sisay-Joof, F.,
tools to integrate genetic and important phenotypic
Pinder, M., Sabeti, P., Kwiatkowski, D.P., Rockett,
information on maps, and devising analytical methods to
K.A. Allelic heterogeneity of G6PD deficiency in
identify genetic regions (e.g. structural variants) that
West Africa and severe malaria susceptibility. Eur
associate with important disease phenotypes of host
J Hum Genet, 2009; 17(8):1080-5
and pathogens (e.g. drug resistance). Taane is a
member of the LSHTM Malaria Centre and is involved in
Teo, Y.Y., Fry, A.E., Bhattacharya, K., Small, K.S.,
establishing a new genetic epidemiology centre. He is
Kwiatkowski, D.P., Clark, T.G. Genome-wide
collaborating on school-initiated genome-wide
comparisons of variation in linkage disequilibrium.
association studies in developing countries, co-initiating
Genome Res, 2009; 19(10):1849-60
global genetic diversity projects of Mtb, and provides
statistical / epidemiology support and training to the
Malaria Genomic Epidemiology Network and pathogen
groups at the WTSI.
Department of Pathogen Molecular Biology
Page 12 of 18
Dr Johannes Dessens, Senior Lecturer in Cell and Molecular Biology
The work focuses on the molecular genetics of malaria
Selected publications
parasites using the rodent malaria parasite model
Plasmodium berghei. Central to this work is the
Khater, E.I., Sinden, R.E., and Dessens, J.T. (2004).
generation of genetically modified parasites in which
A malaria membrane skeletal protein is essential for
target genes are disrupted, tagged or mutated,
normal morphogenesis, motility and infectivity of
providing important information on the expression,
sporozoites. J Cell Biol 167:425-432.
subcellular localization, function and redundancy of
gene products. Dr Dessens was one of the first in the
Carter, V., Shimizu, S., Arai, M., and Dessens, J.T.
UK to successfully establish the gene targeting
(2008). PbSR is synthesized in macrogametocytes
technology in P. berghei and has since applied the
and involved in formation of the malaria crystalloids.
technology to shed light on the function of many
Mol Microbiol 68: 1560-1569.
different Plasmodium genes. The emphasis of his work
is on the molecular and cell biological characterisation
Tremp, A.Z., Khater, E.I., and Dessens, J.T. (2008).
of new genes, in particular those expressed in the
IMC1b is a putative membrane skeleton protein
mosquito stages: ookinetes, oocysts and sporozoites,
involved in cell shape, mechanical strength, motility
with the aim to discover new ways to reduce parasite
and infectivity of malaria ookinetes. J Biol Chem
transmission. Current successful research projects
283: 27604-27611.
involve studies of a family of LCCL proteins involved in
sporozoite development and infectivity (Carter et al.,
Saeed, S., Carter, V. Tremp, A.Z., and Dessens,
2008; Saeed et al., 2010); and a family of membrane
J.T. (2010). Plasmodium berghei crystalloids contain
skeleton proteins involved in parasite shape, motility
and mechanical strength (Khater et al., 2004; Tremp et
multiple LCCL proteins. Mol Biochem Parasitol 170:
al., 2008). The team have expertise in parasite genetic
49-53.
manipulation, mosquito infection and parasite
transmission, electron and confocal microscopy, and in
vitro culture of ookinete, oocyst and sporozoite stages.
They have also pioneered dual tagging of the same
protein at different ends with enhanced green
fluorescent protein and mCherry red fluorescent protein
(Carter et al., 2008), which has opened the door for the
application of fluorescent resonance energy transfer
(FRET) to study protein interactions in live parasites.
Department of Pathogen Molecular Biology
Page 13 of 18
Dr Nick Dorrell, Senior Lecturer in Bacterial Pathogenesis
Current research interests cover
Selected publications
four main areas of bacterial
Corcionivoschi, N., Clyne, M., Lyons, A., Elmi, A.,
pathogenesis relating to the
human pathogens Campylobacter
Gundogdu, O., Wren, B.W., Dorrell, N., Karlyshev,
A.V., Bourke, B. 2009. Campylobacter jejuni
jejuni and Helicobacter pylori.
cocultured with epithelial cells reduces surface
Studies into the regulation of C.
capsular polysaccharide expression. Infect Immun
jejuni gene expression have
77:1959-1967.
identified Cj1556 as a
transcriptional regulatory protein with a role in
Zilbauer, M., Dorrell, N., Elmi, A., Lindley, K.J.,
controlling the bacterial oxidative and aerobic stress
Schuller, S., Jones, H.E., Klein, N.J., Nunez, G.,
responses. An investigation into the role of bacterial
Wren, B .W., Bajaj-Elliott, M. 2007. A major role for
outer membrane vesicles (OMVs) in C. jejuni
pathogenesis has identified over 120 C. jejuni proteins
associated with OMVs and shown that C. jejuni OMVs
intestinal epithelial nucleotide oligomerization
domain 1 (NOD1) in eliciting host bactericidal
immune responses to Campylobacter jejuni. Cell
alone are capable of inducing a host innate immune
Microbiol 9:2404-2416.
response. Ongoing studies into the development of
models of infection have lead to the use of a Vertical
Diffusion Chamber (VDC) to study C. jejuni interactions
Gundogdu, O., Bentley, S.D., Holden, M.T., Parkhill,
J., Dorrell, N., Wren, B.W. 2007. Re-annotation and
with and invasion of intestinal epithelial cells (IECs)
under microaerobic conditions at the apical surface and
aerobic conditions at the baso-lateral surface. Using this
re-analysis of the Campylobacter jejuni NCTC11168
genome sequence. BMC Genomics 8:162.
VDC system, we have demonstrated increased levels of
Kamal, N., Dorrell, N., Jagannathan, A., Turner,
C jejuni interactions with and invasion of IECs and an
S.M., Constantinidou, C., Studholme, D.J., Marsden,
increase in the host innate immune response and are
G., Hinds, J., Laing, K.G., Wren, B.W., Penn, C.W.
currently using the VDC system to investigate the
2007. Deletion of a previously uncharacterized
mechanisms and outcomes of C. jejuni invasion of
flagellar-hook-length control gene fliK modulates the
IECs. Studies are also ongoing into the formation and
sigma54-dependent regulon in Campylobacter
role in pathogenesis of H. pylori biofilms.
jejuni. Microbiology 153:3099-3111.
Department of Pathogen Molecular Biology
Page 14 of 18
Dr Ruth McNerney, Senior Lecturer in Pathogen Biology and Diagnostics
Translational
research
is
undertaken by Ruth McNerney's
group whose research includes
the development, adaptation and
evaluation of tools for the control
of
tuberculosis.
laboratory is experienced in molecular techniques and
immunoassay and previously developed a simple, rapid,
test
for
drug
Mallard, K., Sharaf Eldin, G., McNerney, R.
ScreenTape as a tool for the rapid differentiation of
Mycobacterium tuberculosis isolates. J Med
Microbiol. 2009; 58:1266-8.
This includes
diagnosis and detection of drug resistance. The
low-cost
Selected publications
susceptibility
using
bacteriophages. Point-of-care tests are a major theme
and current activities include the application of artificial
nose technology and novel molecular techniques for the
diagnosis of tuberculosis. Patient based educational
Temple, B., Ayakaka, I., Ogwang, S., Nabanjja, H.,
Kayes, S., Nakubulwa, S., Worodria, W., Levin, J.,
Joloba, M., Okwera, A., Eisenach, K.D.,
McNerney, R., Elliott, A.M., Smith, P.G., Mugerwa,
R.D., Ellner, J.J., Jones-López, E.C.. Rate and
amplification of drug resistance in previously-treated
tuberculosis patients in Kampala, Uganda. Clinical
Infectious Diseases. 2008; 47(9):1126-3.
materials to assist diagnosis by improving the quality of
expectorated sputum have been developed and are
being evaluated in several countries.
The second
theme of research is disease transmission. The
laboratory undertakes DNA fingerprinting and other
PCR based technologies and sequence based analysis
McNerney R, Wondafrash B, A, Amena K, Tesfaye
A, McCash E.M and Murray N.J Field test of a
novel detection device for Mycobacterium
tuberculosis antigen in cough. BMC Infectious
Diseases. 2010; 10:161.
to differentiate strains of tuberculosis and investigate
the emergence of drug resistant forms of the disease.
The laboratory collaborates with a number of projects in
countries with a high burden of tuberculosis, including
Malawi, South Africa and Zimbabwe.
Everett, D.B., Baisley, K.J., McNerney, R.,
Hambleton, I., Chirwa, T., Ross, D.A.,
Changalucha, J., Watson-Jones, D., Helmby, H.,
Dunne, D.W., Mabey, D., Hayes, R.J. 2010
Association of schistosomiasis with false positive
HIV test results in an African adolescent population.
J Clin Micro. 2010; 48(5):1570-7
Department of Pathogen Molecular Biology
Page 15 of 18
Dr Cally Roper, Senior Lecturer
Since 2000 Dr Roper has
Selected publications
worked on practical questions
surrounding the drug treatment
Naidoo ,I., Roper, C. Following the Path of Most
of P. falciparum malaria and its
Resistance. The geographic dispersal of the dhps
impact on resistance evolution.
K540E mutation in African Plasmodium falciparum.
Research funded by her
Trends in Parasitology (2010)
Wellcome Trust fellowship
described how resistance mutations in the dhfr and
Pearce, R. , Pota, H. , Evehe M.B. , El Hadj Bâ ,
dhps genes emerged and spread globally (Roper et al
Mombo-Ngoma, G. , Malisa A. , Ord R. , Inojosa W. ,
2004) and within Africa (Roper et al 2003). Large
Matondo A., Diallo D.A. , Mbacham W., van den
regions of the chromosome around drug resistance
Broek I.V. , Swarthout T. D., Assefa, A. Dejene, S. ,
mutations are affected by selective sweeps in Africa
Grobusch, M.P. , Njie, F. Dunyo, S., Kweku, M.,
even where recombination rates are high (Pearce et al
Owusu-Agyei, S., Chandramohan, D. , Bonnet M. ,
2005) and the team used these linked regions to map
Guthmann J-P. , Clarke, S. , Barnes K.I. , Streat E. ,
the dispersal of drug resistant lineages across Africa
Katokele S. T., P. Uusiku , Agboghoroma, C.O. ,
(Pearce et al 2009), and to describe the emergence of
Elegba O. Y. , Cissé B., A-Elbasit, I. E. , Giha, H.A.
highly resistant dhfr in East Africa (Lynch et al 2008). By
, Kachur, S.P. , Lynch, C., Rwakimari, J. , Chanda,
collating all published dhfr and dhps mutation data, the
P. , Hawela, M. , Sharp B. , Naidoo I., Roper, C.
spatial and temporal spread of resistance mutations in
Multiple origins and regional dispersal of resistant
Africa has been mapped (Naidoo and Roper 2010) and
dhps in African P. falciparum malaria. PLoS
a database and publically available web-based resource
Medicine (2009) 6(4):e1000055
has been created http://drugresistancemaps.org/which
was used to guide WHO policy recommendations on
Lynch, C., Pearce, R., Pota, H., Abeku, Terakegn,
SP-IPTi. The maps of mutation distribution in Africa also
Cox, J., Rwakimari, J., Tibenderand, J., Roper, C.
feature on the Worldwide Antimalarial Resistance
The emergence of highly resistant dhfr alleles in
Network (WWARN) website
P. falciparum populations of SW Uganda. The
http://www.wwarn.org/modules/molecular.
Journal of Infectious Diseases (2008), 197, 15981604.
Plowe, et al., World Antimalarial Resistance
Network (WARN) III: Molecular markers for drug
resistant malaria. (2007) Malaria Journal 6: 121
Department of Pathogen Molecular Biology
Page 16 of 18
Dr Richard Stabler (RCUK Academic Fellow) Lecturer of Molecular Bacteriology
Since joining the LSHTM Dr
Stabler has been involved in two
Selected publications
main projects including the
Stabler, R.A., Gerding, D.N., Songer, J.G., Drudy,
genomic analysis of the
D., Brazier, J.S., Trinh, H.T., Witney, A.A., Hinds, J.,
important nosocomial infection
Wren, B.W., Comparative Phylogenomics of
Clostridium difficile. Initially he
Clostridium difficile Reveals Clade Specificity and
used a whole genome
Microevolution of Hypervirulent Strains. J Bacteriol,
microarray in combination with
2006; 188(20):7297-305
Bayesian statistics (Comparative phylogenomics) to
analyse a diverse collection of animal and clinical
Stabler, R.A., He, M., Dawson, L., Martin, M.,
isolates. This identified for the first time that
Valiente, E,. Corton, C., Lawley, T.D., Sebaihia, M.,
hypervirulent isolates from diverse geographical
Quail, M.A., Rose, G., Gerding, D.N., Gibert, M.,
locations were due to the spread of hypervirulent clones
Popoff, M.R., Parkhill, J., Dougan, G., Wren, B.W.,
[1]. The team were able to use this information to select
Comparative genome and phenotypic analysis of
two examples, one historic and one modern, of the
Clostridium difficile 027 strains provides insight into
PCR-ribotype 027 hypervirulent lineage for whole
the evolution of a hypervirulent bacterium. Genome
genome sequencing [2]. This gave an insight into the
Biol, 2009; 10(9):R102
genetics behind the rapid evolution and emergence of
this clone. To further dissect the genetics, high
He, M., Sebaihia, M., Lawley, T.D., Stabler, R.A.,
throughput next generation genome sequencing
Dawson, L.F., Martin, M.J., Holt, K.E., Seth-Smith,
technology was used [3]. The second project involved
H.M., Quail, M.A., Rance, R., Brooks, K., Churcher,
the design and validation of an Active Surveillance of
C., Harris, D., Bentley, S.D., Burrows, C., Clark, L.,
Pathogens (ASP) microarray [4]. The microarray also
Corton, C., Murray, V., Rose, G., Thurston, S., Van
has been designed to monitor gene flux with particular
Tonder, A., Walker, D., Wren, B.W., Dougan, G.,
interest in emerging infectious diseases.
Parkhill, J. Evolutionary dynamics of Clostridium
Dr Stabler is also involved in a project involving the
difficile over short and long time scales. PNAS,
comparative phylogenomics of Listeria monocytogenes.
2010; 107(16):7527-32
Isolates from human, food and environmental sources
have been analysed and the genetics behind
Stabler, R.A., Dawson, L.F., Oyston, P.C., Titball,
persistence is currently being investigated. He is also
R.W., Wade, J., Hinds, J., Witney, A.A., Wren, B.W.
involved in a number projects looking at virulence
Development and application of the active
factors from Streptococcus pneumoniae, Shigella
surveillance of pathogens microarray to monitor
sonnei and Campylobacter jejuni isolates.
bacterial gene flux. BMC Microbiol, 2008; 8:177
Department of Pathogen Molecular Biology
Page 17 of 18
Michael Gaunt, (RCUK Academic Fellow) Lecturer
The work focused on using
Selected publications
evolutionary models to understand
the molecular epidemiology or
Gaunt, M.W., Yeo, M., Frame, I.A., Stothard, J.R.,
“microevolution” and
Carrasco, H.J., Taylor, M.C., Mena, S.S., Veazey,
“macroevolution” of the parasite
P., Miles, G.A., Acosta, N., de Arias, A.R., Miles,
Trypanosoma cruzi the causative
M.A. (2003). Mechanism of genetic exchange in
agent of South American trypanosomiasis and its insect
American trypanosomes. Nature 421:936-9.
vector triatomine bugs.
Microevolution: T. cruzi is a zoonose and the genetic
Patterson & Gaunt (in press) Phylogenetic
relationship, or “population structure”, between sylvatic
multilocus codon models and molecular clocks
mammals and human reservoir hosts could have
reveal the monophyly of haematophagous reduviid
important public health implications. The team have
bugs and their evolution at the formation of South
developed a population genomics method using
America. Mol Phyl Evol
“microsatellite” genetic markers that provide the most
accurate typing tool available for T. cruzi. The
Llewellyn, M.S., Miles, M.A., Carrasco, H.J., Lewis,
application of this tool to field isolates demonstrates T.
M.D., Yeo, M., Vargas, J., Torrico, F., Diosque, P.,
cruzi has a complex epidemiology. For example, some
Valente, V., Valente, S.A., Gaunt, M.W. (2009)
ecotopes show a close genetic association between
Genome-scale multilocus microsatellite typing of
sylvatic hosts (rodents) and humans but other ecotopes
Trypanosoma cruzi discrete typing unit I reveals
(opossums) show a mixture of close and distant genetic
phylogeographic structure and specific genotypes
associations. The microsatellites panel identified
linked to human infection. PLoS Pathog
multiclonal infections as being much more important
5:e1000410
than previously thought.
Llewellyn, M.S., Lewis, M.D., Acosta, N., Yeo, M.,
Macroevolution: Evolutionary studies on triatomine
Carrasco, H.J., Segovia, M., Vargas, J., Torrico,
bugs revealed the insect evolved blood-feeding
F., Miles, M.A., Gaunt, M.W. (2009) Trypanosoma
behaviour once and this occurred exactly at the same
cruzi IIc: phylogenetic and phylogeographic
time as the formation of South America. Finally,
insights from sequence and microsatellite analysis
theoretical work on evolutionary models reveals that
and potential impact on emergent Chagas disease.
several commonly used assumptions (mutation
PLoS Negl Trop Dis 3: e510
matrices) may result in erroneous epidemiological
inferences. Refining these models provides new
epidemiological insights.
Department of Pathogen Molecular Biology
Page 18 of 18