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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 Page 1 of 18 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 Page 2 of 18 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 Page 3 of 18 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 Page 4 of 18 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 Page 5 of 18 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 Page 6 of 18 David Conway, Professor of Biology Department of Pathogen Molecular Biology Page 7 of 18 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 Page 8 of 18 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 Page 9 of 18 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 Page 10 of 18 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