Department of Pathogen Molecular Biology Academic Staff Profiles

Head of Department: David Conway Department Research Degree Co-ordinator: Sam Alsford Department Operating Officer: Evelyn Sawyer Tel: +44 (0)20 7927 2639 Fax: +44 (0)20 7927 2739

Contents

Mission statements ................................................................................................ p3

Academic staff Professor David Conway (Head of Department) ...................................................... p5 Professor Brendan Wren (Head of Faculty) ............................................................. p6 Professor David Baker ............................................................................................ p7 Professor Mike Blackman......................................................................................... p8 Professor Taane Clark ............................................................................................. p9 Professor Martin Hibberd ....................................................................................... p10 Professor John Kelly .............................................................................................. p11 Professor Michael Miles ......................................................................................... p12 Professor Polly Roy ................................................................................................ p13 Professor Nick Thomson ........................................................................................ p14 Dr Graham Clark .................................................................................................... p15 Dr Ursula Gompels ................................................................................................. p16 Dr Cally Roper ........................................................................................................ p17 Dr Sam Alsford ....................................................................................................... p18 Dr Stephen Baker ................................................................................................... p19 Dr Susana Campino ……………………………………………………………………. p20 Dr Johannes Dessens ............................................................................................ p21 Dr Nick Dorrell ........................................................................................................ p22 Dr Richard Stabler .................................................................................................. p23 Dr Martin Taylor ..................................................................................................... p24 Dr Teresa Cortes ………………………………………………………………………...p25 Dr Jon Cuccui ......................................................................................................... p26 Dr Lisa Dawson ...................................................................................................... p27 Dr Nick Furnham .................................................................................................... p28 Dr Michael Gaunt ................................................................................................... p29 Dr Esmeralda Valiente ........................................................................................... p30

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Mission statements London School of Hygiene and Tropical Medicine 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. Researchers have expertise 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. Faculty of Infectious and Tropical Diseases (ITD) ITD encompasses laboratory-based research as well as clinical and interventional studies 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 work. 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 (PMB) Research in PMB focuses on the molecular biology and genetics of pathogens and their hosts, in order to improve the understanding and control of infectious diseases. Core areas of our research include: (i) determining mechanisms of infection used by diverse eukaryotic, bacterial and viral pathogens, (ii) studying immune evasion mechanisms of pathogens, (iii) understanding genetic diversity and evolution of pathogens, (iv) exploiting particular pathogens as model biological systems, and (v) developing practical applications including improved diagnostics, antimicrobials and P a g e 3 | 30

vaccines. Research in the department focuses on causes of malaria (Plasmodium species), Chagas disease (Trypanosoma cruzi), African sleeping sickness (Trypanosoma brucei), amoebic dysentery (Entamoeba), the Leishmania species, food borne pathogens (Campylobacter jejuni and Yersinia enterocolitica), causes of gastric ulcers and cancer (Helicobacter pylori), pseudomembranous colitis (Clostridium

difficile),

plague

(Yersinia

pestis),

melioidosis

(Burkholderia

pseudomallei), tuberculosis (Mycobacterium tuberculosis), bacterial pneumonia (Streptococcus

pneumoniae),

bluetongue

virus,

herpesviridae,

and

enteric

rotaviruses. Collaborations We have outstanding collaborations with many scientists internationally, including those in disease endemic countries. Many members of PMB spend time at overseas research sites, and have major roles in research in Africa, South America and South East Asia. We also frequently host academics and students on research visits to London as an integral part of these collaborations. PMB has also played a major role in establishing strategic partnerships between LSHTM and other major UK research institutions. This includes a strong alliance with the Wellcome Trust Sanger Institute, and we are planning for collaboration with programmes being established at the Francis Crick Institute. A particularly important new initiative is the formation of the Bloomsbury Research Institute (BRI), a substantial venture between University College London and LSHTM. The BRI will bring together key basic science and translational approaches from across both institutions to provide an optimal environment to develop new drugs, vaccines and diagnostics.

More details on the PMB Department can be found on www.lshtm.ac.uk/itd/pmbd/

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H e a d o f D e pa rt m e n t

David Conway Professor of Biology David Conway has developed several successive research programmes based in London and in Africa. One of his major interests is mechanisms of selection operating on parasites in natural populations and in laboratory culture, as understanding these should help guide development of new interventions as well as use of existing ones. For example, extracellular malaria parasite merozoites in the blood use a range of different receptors to invade erythrocytes. His research aims to understand how enough of them survive and reproduce in the face of acquired immunity, and how future interventions such as blood stage vaccines might have an impact. Use of population genetic analyses, conducted at the whole genome scale, enables investigation to be subsequently focused on particular candidate genes and their products. The relevance of parasite proteins as targets of acquired immunity in humans is studied by correlation of immune responses with risk of clinical malaria. The focus is mostly on Plasmodium falciparum in African populations with diverse endemicity and levels of immunity. This enables comparisons of results across populations in order to test and refine hypotheses, and improve design of experiments to validate molecular targets and mechanisms. He also works on molecular epidemiology of Plasmodium knowlesi in Southeast Asia, and has previously conducted research on trachoma and intestinal nematode infections. Selected publications 1. Admixture in humans of two divergent Plasmodium knowlesi populations associated with different macaque host species. Divis PCS et al. PLOS Pathogens 2015. 2. Comparison of genomic signatures of selection on Plasmodium falciparum in different regions of a highly endemic country. Duffy CW, et al. BMC Genomics 2015. 3. Population genomic structure and adaptation in the human malaria parasite Plasmodium knowlesi. Assefa SA, et al. Proc Natl Acad Sci USA 2015. 4. Genome-wide analysis of selection on the malaria parasite Plasmodium falciparum in West African populations of differing infection endemicity. Mobegi VA, et al. Mol Biol Evol 2014. 5. Population genomic scan for candidate signatures of balancing selection to guide antigen characterization in malaria parasites. Amambua-Ngwa A, et al. PLOS Genetics 2012. www.lshtm.ac.uk/aboutus/people/conway.david

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H e a d o f F a c u l ty

Brendan Wren Professor of Microbial Pathogenesis Brendan Wren’s research interests include determining the genetic basis by which bacterial pathogens cause disease. Research on individual pathogens include; Clostridium difficile, Campylobacter jejuni, Helicobacter pylori, Burkholderia pseudomallei, Coxiella burnetti, Vibrio cholerae, Acitinobacillus pleuropneumoniae, Streptococcus suis, Streptococcus pneumonia and the enteropathogenic Yersinia. The research group exploits a range of post genome research strategies to gain a comprehensive understanding of how these pathogens function, how they evolve and how they interact with their respective hosts. Comparative phylogenomics is used to study the phylohistory and phylogeography of the bacteria we study, which provide clues to the evolution of bacterial virulence. Another major research area is understanding the role of glycosylation in bacterial pathogenesis. This basic research has led to practical applications in the cloning and expression of bacterial glycan structures in E. coli with the development of Protein Glycan Coupling Technology for the construction of new and inexpensive glycoconjugate vaccines for human and animal diseases.

Circular representation of the plague bacterial genome

Selected publications 1. Genomic signatures of human and animal disease in the zoonotic pathogen Streptococcus suis. Weinert LA, et al. Nature Comm 2015. 2. The post translational modification of the Clostridium difficile flagellin affects motility, cell surface properties and virulence He M, et al. Molecular Microbiology 2014. 3. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. He M, et al. Nature Genetics 2013. 4. Exploitation of bacterial N-linked glycosylation to develop a novel recombinant glycoconjugate vaccine against Francisella tularensis. Cuccui J, et al. Open Biology 2013. 5. Bacterial pathogenomics. Pallen M & Wren B. Nature 2007.

www.lshtm.ac.uk/aboutus/people/wren.brendan

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David Baker Professor of Malaria Parasite Biology David Baker’s research is focused on determining the role of cyclic nucleotide signalling in regulating progression of the P. falciparum life cycle. Work from the Baker group has shown essential roles for the cGMP-dependent protein kinase (PKG) in gametocyte activation and ookinete motility in the mosquito stages and in merozoite egress and invasion in the blood stages. David Baker recently received a Wellcome Trust Senior Investigator Award (jointly with Professor Mike Blackman from the Francis Crick Institute) to dissect the role of cGMP signalling in the P. falciparum blood stages. David’s group is also investigating enzymatic components of the cyclic nucleotide signalling pathways as novel antimalarial drug targets with recent grant from the Medical Research Council and the GSK Open lab Foundation in Tres Cantos, Spain.

A chemical genetic approach to determine the role of PKG during life cycle progression

Selected publications 1. Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion. Alam, et al. Nat Commun 2015. 2. cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission Ramdani, et al. PLoS Pathog 2015. 3. Crystal Structures of the Carboxyl cGMP Binding Domain of the Plasmodium falciparum cGMP-dependent Protein Kinase Reveal a Novel Capping Triad Crucial for Merozoite Egress. Kim et al. PloS Pathog 2015. 4. Phosphoinositide biosynthesis links cGMP-dependent protein kinase to essential Ca2+ signals at key decision points in the life cycle of malaria parasites. PLoS Biol 2014. 5. A transcriptional switch underlies commitment to sexual development in human malaria parasites. Kafsack, et al. Nature 2014.

http://www.lshtm.ac.uk/aboutus/people/baker.david

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Mike Blackman Professor of Molecular Parasitology

  

Mike Blackman’s research focuses on the biology of Plasmodium falciparum, the agent of the most dangerous form of malaria. His work aims to understand the molecular mechanisms by which the parasite enters and exits its host cell, and to dissect the structural changes that occur in the host erythrocyte and at the parasite surface during invasion and egress. A major aim is to translate this information into health benefits by identifying drug-like inhibitors of enzymes and other parasite molecules involved in egress and invasion. Current research focuses on: The proteolytic pathway that leads to egress, initiated by a malarial serine protease called SUB1. The kinase-mediated signalling events that trigger egress. Red blood cell invasion and the parasite enzymes and ligands involved. Selected publications 1. Processing of Plasmodium falciparum merozoite surface X-ray crystal structure of SUB1, a protein MSP1 activates a spectrin-binding function protease essential for release of enabling parasite egress from RBCs. Das S, et al. Cell Host malaria parasites from red blood cells & Microbe 2015. 2. The malaria parasite egress protease SUB1 is a calciumdependent redox switch subtilisin. Withers-Martinez C, et al. Nature Communications 2014. 3. Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress. Collins CR, et al. PLoS Pathogens 2013. 4. Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes. Moon RW, et al. Proc Natl Acad Sci USA 2013. 5. Juxtamembrane shedding of Plasmodium falciparum AMA1 is sequence independent and essential, & helps evade invasion-inhibitory antibodies. Olivieri A, et al. PLoS Pathogens 2013.

http://www.lshtm.ac.uk/aboutus/people/blackman.mike

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Taane G. Clark Professor of Genomics and Global Health Taane Clark’s research interests include using high throughput genotyping and sequencing technologies to understand the causes of infectious diseases. This work involves leading global collaborations, developing methods to exploit ‘omic technologies and data in research and clinical settings, and building capacity in infectious disease ‘omics and epidemiology.

Selected projects include:  Using human GWAS approaches to understanding genetic factors underlying malaria susceptibility and immunology;  Understanding malaria parasite diversity through whole genome sequencing, population genetic analysis, and developing molecular barcoding tools.  Detection of novel mutations involved in M. tuberculosis drug resistance and virulence using whole genome sequencing, association and evolutionary analysis;  Elucidating tuberculosis host-pathogen interactions using high throughput genomic technologies. Selected publications 1. Polymorphisms in USP38, FREM3, SDC1, DDC and LOC727982 genes and differential susceptibility to severe malaria phenotypes in Tanzania. Manjurano A, et al. J Infectious Dis 2015. 2. African Glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania. Manjurano A, et al. PloS Genetics 2015. 3. Rapid determination of anti-TB drug resistance from whole-genome sequences. Coll, et al. Genome Medicine 2015. 4. A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains. Preston MD, et al. Nature Commun 2014. 5. A robust SNP barcode for typing Mycobacterium tuberculosis complex strains. Coll, et al. Nature Comm 2014.

pathogenseq.lshtm.ac.uk http://www.lshtm.ac.uk/aboutus/people/clark.taane

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Martin Hibberd Professor of Emerging Infectious Diseases Martin Hibberd’s career has progressed from microbiology to human genetics and now concentrates on genomic sciences for a variety of infections. Since the emerging infectious disease SARS outbreak, it has become clear that genomic and holistic approaches to infectious diseases can give rapid tools for public health impact. These approaches can give novel and sometimes unexpected insights into the disease. These may be turned into diagnostics, prognostics and therapeutic targets. Utilizing human population diversity to understand host-pathogen interactions has revealed specific disease control mechanisms. Looking at the host response to infection on a global scale can identify the rapid temporal changes and the critical points in the disease. Whole genome pathogen investigations complete the molecular picture and inform on the transmission process. Genomic hypotheses require molecular confirmation; for example, macrophage cells respond to TB infection with distinct TLR proteins. Combining these approaches can lead to strong insights and accurate models of the disease process that can be used to identify novel intervention strategies. Using both pathogen and host diversity is also key to understanding the A microarray expression profile of dengue patients identifies novel dynamic process of molecular processes that occur before disease onset. interaction, that is now known to be modified by other infectious agents, or through an interaction with commensal communities. Selected publications 1. Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. Phelan J, et al. BMC Med 2016. 2. Genomic approaches for understanding dengue: insights from the virus, vector, and host. Sim S, Hibberd ML. Genome Biol 2016. 3. Chronic Infection With Camelid Hepatitis E Virus in a Liver Transplant Recipient Who Regularly Consumes Camel Meat and Milk. Lee GH, et al. Gastroenterology 2016. 4. Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution. Do LA, et al. J Gen Virol 2015. 5. Variation at HLA-DRB1 is associated with resistance to enteric fever. Dunstan SJ, et al. Nat Genet 2014.

www.lshtm.ac.uk/aboutus/people/hibberd.martin

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John Kelly Professor of Molecular Biology John Kelly’s main research interests focus on the parasitic protozoan Trypanosoma cruzi, which is responsible for Chagas disease. This infection represents a major public health problem in Latin America, and is increasingly being detected in nonendemic regions because of migration. Advances by ourselves, and others have led to the generation of a wide range of genetic tools that can be used to address fundamental biological questions associated with these important pathogens. In addition, highly sensitive imaging technology that we have developed is providing a research framework where rapid progress can be expected. We are exploiting these new approaches and opportunities to T. cruzi replicating amastigote gain greater understanding of the mechanisms of drug action forms (red dots) inside infected and resistance, and disease pathogenesis. In collaboration mammalian cells. with biologists, biochemists and organic chemists, we 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 both academic and industrial partners, is widely seen as the way ahead to provide better treatments for this previously ‘Neglected Diseases’. T. cruzi insect stage epimastigote form.

Selected publications 1. Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy. Lewis M, et al. Cellular Microbiology 2016. 2. The limited ability of posaconazole to cure both acute and chronic Trypanosoma cruzi infections revealed by highly sensitive in vivo imaging. Fortes Francisco A., et al. Antimicrob Agents Chemother 2015. 3. Bioluminescence imaging of chronic Trypanosoma cruzi infections reveals tissue-specific parasite dynamics and heart disease in the absence of locally persistent infection. Lewis M. et al.Cellular Microbiology 2014. 4. Evidence that transport of iron from the lysosome to the cytosol in African trypanosomes is mediated by a mucolipin orthologue. Taylor M, et al. Molecular Microbiology 2013. 5. Benznidazole-resistance in Trypanosoma cruzi is a readily acquired trait that can arise independently in a single population. Mejia A, et al. J. Infectious Diseases 2012.

www.lshtm.ac.uk/aboutus/people/kelly.john

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Michael Miles Professor of Medical Protozoology Michael Miles’s research is primarily focused on Trypanosoma cruzi, the agent of Chagas disease (South American trypanosomiasis) and on Leishmania species, the agents of visceral (VL) and mucocutaneous leishmaniasis (MCL), encompassing fundamental laboratory research and fieldwork in endemic areas. Principal research interests are the presence, importance and mechanisms of genetic exchange in experimental and natural populations of these organisms, and the molecular epidemiology of Chagas disease and the leishmaniases in the context of improvement of control strategies. Other interests are comparative genomics, diagnostics development, the ecology and population genetics of triatomine bugs, the ecology and behaviour of South American mammals, and the control of African trypanosomiasis. Recent achievements of the research group include the first experimental proof of genetic exchange in T. cruzi; demonstration that sylvatic Rhodnius prolixus does invade houses in Venezuela, and several detailed population genetics studies of natural populations of T. cruzi using multilocus sequence typing (MLST) and microsatellite analysis (MLMT). Coordinator, of the European/Latin American FP6 network (LeishEpiNetSA), 12 partners, to 2010 - Coordinator (assisted by Martin Llewellyn), of the European/Latin American FP7 network (ChagasEpiNet), 15 partners, to 2012. Selected publications 1. Ecological host fitting of Trypanosoma cruzi TcI in Bolivia: mosaic population structure, hybridization and a role for humans in Andean parasite dispersal. Messenger LA, et al. Mol Ecol. 2015. 2. Deep sequencing of the Trypanosoma cruzi GP63 surface proteases reveals diversity and diversifying selection among chronic and congenital Chagas disease patients. Llewellyn MS, et al. PLoS Negl Trop Dis 2015. 3. Shotgun sequencing analysis of Trypanosoma cruzi I Sylvio X10/1 and comparison with T. cruzi VI CL Brener. Franzen O, et al. PLoS Negl Trop Dis 2011. 4. Recent, independent and anthropogenic origins of Trypanosoma cruzi hybrids. Lewis MD, et al. PLoS Negl Trop Dis 2011. 5. Analysis of molecular diversity of the Trypanosoma cruzi trypomastigote small surface antigen reveals novel epitopes, evidence of positive selection and potential implications for lineage-specific serology. Bhattacharyya T, et al. Int J Parasitol 2010.

www.lshtm.ac.uk/aboutus/people/miles.michael

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Polly Roy Professor of Virology Polly Roy’s salient contribution has been the first completed molecular understanding of the Orbiviruses, of the Reoviridae family, a distinct group of several hundred viruses of serious health and economic impact. Roy used multi-disciplinary approaches to provide a detailed understanding of the Bluetongue virus (BTV), a major Orbiviruses pathogen and model for a range of human and animal viruses with similar structure, including human rotavirus. She has used virology, molecular biology, immunology and structural biology studies as required, examining each aspect of the virus, from individual virus proteins to virus entry, assembly of the complete virus particle and its engagement, at various levels, with the host cell. She has developed improved diagnostic assays, more efficacious vaccines and alternate therapeutic possibilities in the addition to the fundamental scientific advance discovered. Roy’s findings that co-expression of virus structural proteins leads to the assembly of virus-like particles spawned an area of expression technology that has seen the development of many candidate animal and human vaccines. Roy’s team pioneered the first reverse system for BTV (the synthesis of infectious virus solely from synthetic genes), a major achievement for this class of viruses, which has allowed major studies of the genetic basis for pathogenesis and the generation of new efficacious vaccines for orbiviruses. Other ground breaking advances has been the establishment of an outstanding cell-free system to reconstitute infectious BTV particles, a striking example of the use of synthetic biology to generate viruses de novo. Recently using a novel RNA-RNA interaction assay together with cellfree packaging assay, Roy’s team unravel how multisegmented viruses select and package their genome. Roy’s contribution to virology, in particular to virus structure and assembly, has been recognised by her peers worldwide through numerous awards and prizes. Selected publications 1. 2. 3. 4. 5.

Entry of Bluetongue virus capsid requires specific cellular lipid. Patel, et al. Journal of Biological Chemistry 2016. Atomic structure of a non-enveloped virus reveals pH sensors for a coordinated process of cell entry. Zhang X, et al. Nature Structural and Molecular Biology 2016. Disruption of Specific RNA-RNA interactions in a double-stranded RNA virus inhibits genome packaging and virus Infectivity. Fajardo, et al. PLoS Pathogen 2015. Rotavirus NRNAS are released by transcript-specific channels in the double-layered viral capsid. Periz, et al. Proc Natl Acad Sci USA 2013. In vitro reconstitution of Bluetongue virus infectious cores. Lourenco. Proc Natl Acad Sci USA 2011.

http://www.lshtm.ac.uk/aboutus/people/roy.polly

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Nick Thomson Professor of Bacterial Genomics and Evolution Nick Thomson holds a split academic position between the LSHTM and The Wellcome Trust Sanger Institute. During his career he has transitioned from a classically trained Molecular Biologist to a Genome Scientist using high throughput sequencing technologies. His current work involves the application of phylogeny to understand the contemporary or historical distribution of bacterial pathogens causing diarrheal disease, including Shigella sonnei, Vibrio cholerae and Salmonella. His work on cholera used modern techniques and genomic data to identify a global source for pandemic cholera. In addition his group has contributed to a ‘One Health’ look at the flow of antimicrobial resistance (AMR) and the zoonotic pathogen Salmonella Typhimurium DT104 by considering isolates from both humans and farm animals (Fig 1 & 2). He considers studies of this nature and resolution to be essential if we are to identify the sources Figure 1. The phylogenetic relationships of DT104 strains and sinks of both food borne found in animals and humans in pathogens such as DT104 and AMR. being one of ScotlandAMR over a 22 year period. the most important threats to public health. His groups work on Chlamydia showed that despite the pervasive notion that Chlamydia do not recombine, their genomes showed evidence of widespread DNA exchange between isolates affecting different body sites, challenging much of our understanding of C. trachomatis Figure 2. The number of transitions evolution and epidemiology. To facilitate this, his group between animals and humans has developed methods to sequence Chlamydia directly within the phylogeny. from uncultured discarded clinical swabs, a methodology with broad applications in clinical microbiology. Selected publications 1. Chlamydia trachomatis from Australian Aboriginal people with trachoma are polyphyletic composed of multiple distinctive lineages. Andersson, et al. Nat Commun 2016. 2. Global phylogeography and evolutionary history of Shigella dysenteriae type 1. Njamkepo, et al. Nature Microbiology 2016. 3. Species-wide whole genome sequencing reveals historical global spread and recent local persistence in Shigella flexneri. Connor, et al. eLife 2016. 4. Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Holt, et al. PNAS 2015. 5. Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study. Baker, et al. Lancet ID 2015. www.lshtm.ac.uk/aboutus/people/thomson.nick

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Taught Course Director Graham Clark Reader in Molecular Parasitology Graham Clark’s research interests include the genetic diversity and evolution of gut protozoan parasites. The main organisms studied are Entamoeba, which includes E. histolytica, the agent of amoebic dysentery and amoebic liver abscesses, and Blastocystis, an organism of uncertain pathogenicity. Current Research focuses on: Entamoeba  genome re-sequencing as a way to build on earlier results indicating a parasite genetic component linked to the outcome of Entamoeba histolytica infection.  people who develop disease are infected with a different range of genotypes from those who remain asymptomatic. Blastocystis  investigating whether any of the genetic subtypes of the organism are linked to the symptoms found in some individuals.  sequencing its mitochondrial and nuclear genomes in an attempt to understand the function of the mitochondrion in this strictly anaerobic organism. Blastocystis sp.

Selected publications 1. Expanding the Entamoeba universe: new hosts yield novel ribosomal lineages. Jacob AS, et al J Euk Microbiol 2016. 2. Recent developments in Blastocystis research. Clark CG, et al. Adv Parasitol 2013. 3. Genetic diversity of Blastocystis in livestock and zoo animals. Alfellani MA, et al. Protist 2013. 4. Genomic diversity of the human intestinal parasite Entamoeba histolytica. Weedall GD, et al. Genome Biol 2012. 5. Levels of genetic diversity vary dramatically between Blastocystis subtypes. Stensvold CR, et al. Infect Genet Evol 2012.

www.lshtm.ac.uk/aboutus/people/clark.graham

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Ursula Gompels Reader in Molecular Virology Ursula Gompels’ research is on human herpesviruses, recently on the betaherpesvirus subgroup, human herpesvirus 6 (variants HHV-6A and HHV-6B) and human cytomegalovirus (HCMV). These viruses can be significant paediatric pathogens and are major opportunistic infections in immunosuppressed populations, as HIV/AIDS and transplantation patients, causing morbidity and mortality. HHV-6A/B, are emerging pathogens causing fatal encephalitis in immunosuppressed hematopoietic transplant patients and linked to status epilepticus and myocarditis. Betaherpesviruses cause lifelong latent infections adapted to persist in cells of our immune system, and can reactivate to cause disease. Uniquely amongst human herpesvirus, HHV-6A/B integrate in the germline of approximately 1% humans, within the subtelomere of our chromosomes, giving an inherited ‘congenital’ infection. Pathogenic effects are being studied including infant development delays and cardiac disease. The virus encode key immunological adaptations to the host providing a toolbox to devise novel immune-based Human herpesvirus chemokine, medicines. Work is multidisciplinary covering infection ‘virokine’ arrests HIV CCR5 receptor and immune modulation with implications for vaccine (green) at the cell surface. studies and paediatric HIV/AIDS: i) effects of betaherpesvirus on infant development in maternally HIV exposed infants, in collaboration with EPH and the University Teaching Hospital in Zambia, ii) molecular mechanisms of virus entry and iii) virus mimics of inflammatory mediators, chemokine and chemokine receptors, these also inhibit HIV infection, and have major applications to immunotherapeutics and vaccines. Selected publications 1.

2.

3.

4. 5.

Increased Cytomegalovirus Secretion and Risks of Infant Infection by Breastfeeding Duration From Maternal Human Immunodeficiency Virus Positive Compared to Negative Mothers in Sub-Saharan Africa. Musonda K, et al. J Pediatric Infect Dis Soc 2016. Complete Genome Sequence of Germline Chromosomally Integrated Human Herpesvirus 6A and Analyses Integration Sites Define a New Human Endogenous Virus with Potential to Reactivate as an Emerging Infection. Tweedy, et al. Viruses 2016. Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators. Tweedy, et al. J Gen Virol 2015. Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide. Clark, et al. J Gen Virol 2013. Reduced Poliovirus vaccine neutralising-antibody titres in infants with maternal HIVexposure. Vaccine 2013.

www.lshtm.ac.uk/aboutus/people/gompels.ursula

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Cally Roper Reader in Malaria Genetics Cally Roper arrived to LSHTM with a background in Evolution and Population Genetics research. Her interest is in the development and application of novel genetic approaches to questions about malaria treatment and malaria control. In particular, she is interested in resistance to antimalarial drugs and identifying the factors which drive its emergence and geographic dispersal. Current projects include the development of a genetic barcode, mapping resistance mutations in Africa to inform policy on malaria prevention in pregnant women and infants, measuring drug selection applied by the adoption of specific treatment interventions in the field, and assessing the role of human migration in the dispersal of drug resistant malaria. Malaria parasite molecular epidemiology in Sri Lanka

Selected Publications 1. Multiple Origins of Mutations in the mdr1 Gene—A Putative Marker of Chloroquine Resistance in P. vivax. Mette L, et al. PLOS Neglected Tropical Diseases 2015. 2. The influence of malarial transmission intensity and the 581G resistance mutation on the protective effect of intermittent preventive treatment of malaria in pregnancy (IPTp): A systematic review and meta-analysis Chico R, et al. Tropical Medicine and International Health 2015. 3. Barcoding Malaria Parasites: A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains. Preston MD, et al. Nature Communications 2014. 4. Measuring drug pressure in a field trial of intermittent preventive treatment of infants (IPTi). A community-randomised evaluation of the effect of IPTi on antimalarial drug resistance in southern Tanzania. Pearce , R J, et al. The Journal of Infectious Diseases 2013. 5. Multiple origins and regional dispersal of resistant dhps in African P. falciparum malaria. Pearce R, et al. PLoS Medicine 2009.

http://www.lshtm.ac.uk/aboutus/people/roper.cally

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Sam Alsford Senior Lecturer in Molecular Parasitology Sam Alsford’s early work focused on the development of a range of molecular tools for use in the genetic manipulation of Trypanosoma brucei, the causative agent of human African trypanosomiasis (see http://blogs.lshtm.ac.uk/alsfordlab/celllines-plasmids/). This enabled the transition from candidatebased or reverse genetic approaches, to the use of forward genetics in developing our understanding of trypanosome biology. Initially, this technology was applied to understanding the uptake and intracellular transit of the current antiHAT drugs, in particular suramin, and identifying potential routes to resistance2,4. It’s now being used to define parasite’s interaction with other factors, including novel anti-trypanosomatid drugs, nutrients and innate immune factors3.

DNA ELP3a ELP3b

Fig. 2: The nucleolar localization of the rRNA transcriptional regulator, ELP3b.

DNA ISG75

Fig. 1: Distribution of ISG75, a surface protein responsible for suramin uptake.

Sam Alsford is also interested in the control of RNA polymerase I-mediated transcription of rDNA and VSG in T. brucei. This work led to the recent identification of a key regulator of monoallelic VSG expression1, and the identification of a novel role for the Elongator protein, ELP3b, in the differential regulation of rDNA array transcription5.

Selected publications 1. VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes. Glover, et al. Proc Natl Acad Sci 2016. 2. Modulation of the surface proteome through multiple ubiquitylation pathways in African trypanosomes. Zoltner M, et al. PLoS Pathogens 2015. 3. Cathepsin-L can resist lysis by human serum in Trypanosoma brucei brucei. Alsford S, et al. PLoS Pathogens 2014. 4. High-throughput decoding of anti-trypanosomal drug efficacy and resistance. Alsford S, et al. Nature 2012. 5. Elongator protein 3b negatively regulates ribosomal DNA transcription in African trypanosomes. Alsford S & Horn D, Mol Cell Biol 2011.

blogs.lshtm.ac.uk/alsfordlab www.lshtm.ac.uk/aboutus/people/alsford.sam

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Stephen Baker Senior Lecturer in Emerging Infections Stephen Baker heads the enteric infections research group at the Wellcome Trust Major overseas programme (WT-MOP) in Ho Chi Minh City, Vietnam. His group studies the microbiology, genetics, epidemiology and treatment of enteric infections caused by members of the Enterobacteriaceae. The Gram-negative Enterobacteriaceae incorporate a number of enteric pathogens, including pathogenic variants of E. coli (the most common cause of community-acquired diarrhoea), Shigella spp., the cause of shigellosis, and the many serovars of Salmonella enterica, including S. Typhi and S. Paratyphi A, the causative agents of enteric (typhoid) fever. Transmission of the organisms frequently occurs via faecal contamination of food, water and the environment. Thus, the risk of infection with pathogenic members of the Enterobacteriaceae is higher in areas with poor sanitation and hygiene. This is a significant global problem, as acute infectious diarrhoea is the second biggest killer of children, accounting for 21% (~2.5 million annually) of childhood deaths worldwide and S. Typhi and S. Paratyphi A are estimated to cause >25,000,000 new infections annually with >200,000 deaths. Our current focus combines microbiological, immunological and geographical information to study how organisms are transmitted in urban environments and how this interplay can be used to design and implement vaccination strategies. Areas of particular interest include: i) Evolutionary adaptation and clonal replacement of gastrointestinal pathogens, ii) Molecular diagnostics of bacterial pathogens, iii) The impact of antimicrobial resistance, iv) Horizontal gene transfer. v) Epidemiological and clinical aspects of gastrointestinal infections. vi) Randomised controlled trials for enteric infections, vii) Serological markers of infection and pathogen exposure, viii) Genome sequencing and pathogen genotyping. Selected publications 1. A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure. Pham Thanh D, et al. ELife 2016. 2. The Hd, Hj, and Hz66 flagella variants of Salmonella enterica serovar Typhi modify host responses and cellular interactions. Schreiber F, et al. Sci Rep 2015. 3. Epidemiology and Rising Prevalence of Pediatric Symptomatic and Asymptomatic Norovirus Infections in Ho Chi Minh City, Vietnam. My PVT, et al. Emerg Infect Dis 2013. 4. Immune profiling with a Salmonella Typhi antigenmicroarray identifies new diagnostic biomarkers of human typhoid. Liang L, et al. Nature Sci Rep 2013. 5. Shigella sonnei genome sequencing and phylogeneticanalysis indicate recent global dissemination from Europe. Holt KE, et al. Nat Genet 2012.

www.lshtm.ac.uk/aboutus/people/baker.stephen

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Susana Campino Senior Lecturer in Genomics Susana Campino’s main field is the genomic epidemiology of malaria, applied to the human host and Plasmodium parasites. Her research interests include understanding how changes in the genome can affect both response to infection and disease progression in humans, and virulence and response to antimalarial drugs and other control methods (e.g. vaccines) in the parasites. She is also interested in developing tools to improve current malaria infection diagnosis and surveillance of parasites during malaria control interventions. She has a strong background in molecular biology and population genetics and genomics, and started to apply these skills to M. tuberculosis, and Zika and Dengue virus pathogen genomes. Selected projects include:  Exploring the genetic diversity of human malaria parasites through whole genome sequencing and developing diagnostic and molecular barcoding tools. SNPs in P. falciparum organelles  Investigating malaria in pregnancy: Are the parasites sequestered in the placenta genetically different?  Understanding the genetic diversity of P. vivax in Brazil and recrudescent/ reinfection during pregnancy. Selected publications 1. Genomic variation in two gametocyte non-producing P. falciparum clonal lines. Benavente ED, et al. Malaria Journal 2016. 2. Genomic epidemiology of artemisinin resistant malaria. MalariaGEN Elife 2016. 3. K13-propeller polymorphisms in P. falciparum parasites from sub-Saharan Africa. Kamau E, et al. J Infect Dis 2015. 4. A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains. Preston MD, et al. Nature Comm 2014. 5. Analysis of P. falciparum diversity in natural infections by deep sequencing. Manske M, et al. Nature 2012.

http://www.lshtm.ac.uk/aboutus/people/campino.susana

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Johannes Dessens Senior Lecturer in Parasite Cell Biology Research in Johannes Dessens’ lab focuses on the molecular and cell biological characterisation of malaria parasite genes, in particular those expressed in the mosquito stages: ookinetes, oocysts and sporozoites, with the aim to discover new rational ways to reduce parasite transmission. Successful research projects involve studies of a family of LCCL-domain adhesive proteins (LAPs); and a family of cytoskeletal intermediate filament proteins (alveolins). We have shown that LAPs are targeted to the crystalloids, unique multivesicular organelles found uniquely in ookinetes and young oocysts. LAP depletion abolishes crystalloid biogenesis and sporozoite transmission, identifying the crystalloid as a key organelle in sporogonic development. Alveolins are targeted to a unique cortical structure, the subpellicular network (SPN), in merozoites, ookinetes and sporozoites, and alveolin depletion gives rise to morphological abnormalities and reduced motility, tensile strength and infectivity. We have shown that alveolin domains are composed of tandem repeat sequences with a 12 amino acid periodicity.

Cultured P. berghei ookinetes expressing a GFP-tagged alveolin (left), and a GFP-tagged LAP (right), serving as fluorescent markers for the SPN and crystalloids, respectively. Selected publications 1. Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite. Santos JM, et al. Proc Natl Acad Sci USA 2016. 2. Biogenesis of the crystalloid organelle in Plasmodium involves microtubule-dependent vesicle transport and assembly. Saeed S, et al. Int J Parasitol 2015. 3. Plasmodium alveolins possess distinct, but functionally and structurally related multi-repeat domains. Al-Khattaf FS, et al. Parasitol Res 2015. 4. PbSR is synthesized in macrogametocytes and involved in formation of the malaria crystalloids. Carter V, et al. Mol Microbiol 2008. 5. A malaria membrane skeletal protein is essential for normal morphogenesis, motility and infectivity of sporozoites. Khater EI, et al. J Cell Biol 2004.

www.lshtm.ac.uk/aboutus/people/dessens.johannes

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Course Director for MSc in Medical Microbiology

Nick Dorrell Senior Lecturer in Bacterial Pathogenesis Nick Dorrell’s current research interests cover five main areas of bacterial pathogenesis relating to the human pathogen Campylobacter jejuni. Studies into the regulation of C. jejuni gene expression have identified RrpA and RrpB as transcriptional regulatory proteins with a role in controlling peroxide and aerobic stress responses. An investigation into the role of bacterial outer membrane vesicles (OMVs) in C. jejuni pathogenesis has shown that C. jejuni OMVs alone are capable of inducing a host innate immune response and possess proteolytic activity. Investigations into the mechanisms of C. jejuni invasion of intestinal epithelial cells are focusing on the role of the fibronectin-binding proteins CadF and FlpA. Recent studies are also focusing on the role of the C. jejuni Type VI Secretion System. Also investigations into the innate immune response to C. jejuni infection in collaboration with Mona Bajaj-Elliott (UCL Institute of Child Health) have identified novel bacterial interactions with the host immune system. Current research focuses on:     

Role of outer membrane vesicles during C. jejuni infection; C. jejuni oxidative and aerobic stress responses; Mechanisms of C. jejuni invasion of intestinal epithelial cells; Role of the C. jejuni Type VI Secretion System; The innate immune response to C. jejuni infection.

Selected publications 1. Campylobacter jejuni outer membrane vesicle-associated proteolytic activity promotes bacterial invasion by mediating cleavage of intestinal epithelial cell E-cadherin and occludin. Elmi et al. Cell Microbiol 2016. 2. The Campylobacter jejuni MarR-like transcriptional regulators RrpA and RrpB both influence bacterial responses to oxidative and aerobic stresses. Gundogdu, et al. Front Microbiol 2015. 3. Campylobacter jejuni lipooligosaccharide sialylation, phosphorylation, and amide/ester linkage modifications fine-tune human Toll-like receptor 4 activation. Stephenson, et al. J Biol Chem 2013. 4. Campylobacter jejuni outer membrane vesicles play an important role in bacterial interactions with human intestinal epithelial cells. Elmi, et al. Infect Immun 2012. 5. Increase in Campylobacter jejuni Invasion of Intestinal Epithelial Cells under Low-Oxygen Coculture Conditions That Reflect the In Vivo Environment. Mills, et al. Infect Immun 2012.

http://www.lshtm.ac.uk/aboutus/people/dorrell.nick

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Richard Stabler Senior Lecturer of Molecular Bacteriology Richard Stabler’s research interests include the genomic analysis of bacterial pathogens with a current focus on the genetics and transmission of antibiotic resistance. He has exploited emerging technologies, initially genome microarrays but more recently high throughput sequencing technology (HTST) and nanopore technologies (MinION) for molecular epidemiology and identification of genes involved in virulence. He is currently the antimicrobial resistance lead for the school and runs the AMR interest group. Additionally, he is also the LSHTM space business manager due to his links with the European Space Agency. Current research focuses on:  The global population of Clostridium difficile RT023 and Acinetobacter baumannii,  Hospital and community transmission of Methicillin Resistant Staphylococcus Aureus (MRSA) in South London,  Identifying drug resistance and virulence factors from A. baumannii,  The potential role of bacteriophage depolymerases as therapy for A. baumannii infection,  Investigating the genetics essential for colonisation and dissemination of Escherichia coli K1 in neonatal meningitis,  The role of pharyngeal commensals with the development of highly drug resistant Neisseria gonorrhoea,  Analysis of the effect of a Gravity Loading Countermeasure SkinSuit on the natural bacterial skin flora. Selected publications 1. Clonal variation in high- and low-level phenotypic and genotypic mupirocin resistance of MRSA isolates in south-east London. Hughes J, et al. J Antimicrob Chemother 2015. 2. Genomic Epidemiology of a Protracted Hospital Outbreak Caused by a Toxin A-Negative Clostridium difficile Sublineage PCR Ribotype 017 Strain in London, England. Cairns MD, et al. J Clin Microbiol 2015. 3. The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection. McCarthy AJ, et al. Infect Immun 2015. 4. Staphylococcal phenotypes induced by naturally occurring and synthetic membraneinteractive polyphenolic β-lactam resistance modifiers. Palacios L, et al. PLoS One 2014. 5. Draft Genome Sequences of Pseudomonas fluorescens BS2 and Pusillimonas noertemannii BS8, Soil Bacteria That Cooperate To Degrade the Poly-γ-d-Glutamic Acid Anthrax Capsule. Stabler RA, et al. Genome Announc 2013.

www.lshtm.ac.uk/aboutus/people/stabler.richard

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Martin Taylor Senior Lecturer in Molecular Biology Martin Taylor is interested in nutrient uptake and utilisation in Kinetoplastids. His recent work has focused principally on iron and ascorbate (vitamin C). Iron is a crucial nutrient for a variety of pathogenic organisms and can be sequestered by the innate immune system. Martin’s work is centred on the mechanisms used by kinetoplastid parasites to obtain iron in their mammalian host. His primary interest is in the African and American trypanosomes, T. brucei and T. cruzi. T. brucei being extracellular in the mammal of Luciferaseobtains non-heme iron from transferrin by endocytosis. Expression mNeon GFP fusion protein The roles of various proteins in this uptake are currently (green) in Trypanosoma cruzi. being analysed This allows us to follow infection in mice and at the cellular level using a variety of in tissues. techniques including RNA interference, conditional null mutants, drug assays and fluorescence based assays for intracellular iron levels. He has created a conditional expression system for the American trypanosome which will be used to characterise iron uptake pathways in Our current model of iron trafficking in the this intracellular parasite. Martin is also involved blodstream form trypanosome. Incoming in developing highly sensitive in vivo imaging ferric iron is reduced by Cyb561 to ferrous iron. This is transported across the models for drug discovery programmes and membrane by MLP. pathogenesis studies for Human African Trypanosomiasis (Sleeping Sickness), Chagas disease and visceral leishmaniasis. Selected publications 1. Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy. Lewis MD, et al. Cell Microbiol 2016. 2. The Trypanosoma cruzi Vitamin C Dependent Peroxidase Confers Protection against Oxidative Stress but Is Not a Determinant of Virulence. Taylor MC, et al. PLoS Negl Trop Dis 2015. 3. TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei. Shameer S, et al. Nucleic Acids Res 2015. 4. Highly Sensitive In Vivo Imaging of Trypanosoma brucei Expressing “Red-Shifted” Luciferase. McLatchie AP, et al. PLoS Negl Trop Dis 2013. 5. Evidence that transport of iron from the lysosome to the cytosol in African trypanosomes is mediated by a mucolipin orthologue. Taylor MC, et al. Mol Microbiol 2013.

www.lshtm.ac.uk/aboutus/people/taylor.martin

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Teresa Cortes Lecturer in Microbiology Teresa Cortes is funded by a Starting Grant from the European Research Council. She is primarily interested in investigating how translational regulation contributes to biological adaptation in the human pathogen Mycobacterium tuberculosis, the causative agent of human tuberculosis. As well as causing tuberculosis, M. tuberculosis can persist in an individual host for decades in an asymptomatic state, with one third of the world population estimated to be latently infected. The mechanisms underlying this persistence in the host are still poorly understood. Furthermore, the emergence of drug resistant tuberculosis makes the development of effective new treatments an urgent challenge. Understanding the ability of M. tuberculosis to switch between replicating and non-replicating states during infection and disease is central to the search for improved treatments. Recent findings suggest that ‘specialised ribosomes’ can preferentially translate different mRNA subsets, particularly in response to stress. mRNA molecules contain specific signals that optimise their interaction with ribosomes; known as leader sequences, these include the Shine-Dalgarno (SD) sequence required for canonical translation initiation in bacteria. Teresa’s previous research recently demonstrated that M. tuberculosis expresses an unexpected number of leaderless mRNA transcripts that lack the SD sequence. In Escherichia coli, only a few leaderless transcripts have been described and they are selectively translated by specialised ribosomes. Teresa’s group is using cutting-edge experimental techniques combined with bioinformatics analysis to investigate the role of translation regulation in the adaptive response of M. tuberculosis and its contribution to differential susceptibility to drugs that target ribosomal activities. Selected publications 1. Genome-Wide Mapping of Transcriptional Start Sites Defines an Extensive Leaderless Transcriptome in Mycobacterium tuberculosis. Cortes T, et al. Cell Rep 2013. 2. Transcription and translation of the rpsJ, rplN and rRNA operons of the tubercle bacillus. Cortes T and Cox RA. Microbiology 2015. 3. Genomic mapping of cAMP Receptor Protein (CRP Mt) in Mycobacterium tuberculosis: relation to transcriptional start sites and role of CRPMt as a transcription factor. Kahramanoglou C, et al. Nucleic Acids Res 2014. 4. Mapping of genotype-phenotype diversity amongst clinical isolates of Mycobacterium tuberculosis by sequence-based transcriptional profiling. Rose G, et al. Genome Biol Evol 2013. 5. A small RNA encoded in the Rv2660c locus of Mycobacterium tuberculosis is induced during starvation and infection. Houghton J, et al. PLoS One 2013.

http://www.lshtm.ac.uk/aboutus/people/cortes.teresa

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Jon Cuccui Lecturer in Molecular Bacteriology Jon Cuccui has a long standing interest in bacterial glycosylation systems. His initial work at LSHTM using signature tagged mutagenesis in Burkholderia pseudomallei, the causative agent of melioidosis, revealed that the capsular polysaccharide was a major virulence determinant. This research led to improved understanding and exploitation of polysaccharides as vaccine components. He was recently involved in the generation and sequencing of a million mutant transposon (TraDIS) library of B. pseudomallei which Principles of protein glycan technology in E. coli. revealed novel essential genes and targets for antimicrobial development. Understanding bacterial glycosylation systems can reveal why they evolved and were maintained, and secondly, how they can potentially be exploited as novel biotechnological tools. Jon Cuccui is involved in using in vivo glycosylation systems, termed ‘protein glycan coupling technology’ (PGCT) in order to assemble glycoconjugate vaccines. He developed a first generation glycoconjugate vaccine against the Gram negative bacterium, Francisella tularensis, the causative agent of tularemia for which no licensed vaccine currently exists. PGCT has been subsequently used to generate vaccines against the human pathogens B. pseudomallei and Streptococcus pneumoniae. More recently he has been developing novel genetic tools to expand the utilisation of PGCT to subunit vaccine generation against animal pathogens. He is funded by a Wellcome Trust/LSHTM fellowship to identify and overcome glycoengineering bottlenecks in order to expand the capabilities of PGCT. He is also studying the N-linked glycosylation system in the porcine pathogen A. pleuropneumoniae and attempting to unravel its biological function and potential application. Selected publications 1. Recombinant expression of Streptococcus pneumoniae capsular polysaccharides in Escherichia coli. Kay EJ, et al. Open Bio. J. 2016. Epub 2016. 2. Functional analysis of N-linking oligosaccharyl transferase enzymes encoded by deep-sea vent proteobacteria. Mills DC, et al. Glycobiology 2016. 3. Exploitation of bacterial N-linked glycosylation to develop a novel recombinant glycoconjugate vaccine against Francisella tularensis. Cuccui J, et al. Open Biol 2013. 4. Genome-wide saturation mutagenesis of Burkholderia pseudomallei K96243 predicts essential genes and novel targets for antimicrobial development. Moule MG, et al. MBio 2014.

www.lshtm.ac.uk/aboutus/people/cuccui.jon

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Lisa Dawson Lecturer Lisa Dawson sits on the Senate and Athena swan committee. She is also a member of the exam board for the Medical Microbiology and Molecular Biology of Infectious Diseases MSc courses and a tutor for both Distance Learning MSc and Medical Microbiology MSc courses. She supervises both PhD and MSc research projects based at LSHTM. Her research interests also include Mycobacterium tuberculosis. She undertook a PhD at the National Institute for Medical Research, in which Lisa studied the regulation of DNA damage repair in Mycobacterium tuberculosis. The main focus of the research is the characterisation of the genetic and phenotypic traits of the pathogenic bacteria, including Clostridium difficile using a genome to phenome approach. Clostridium difficile is the most frequent cause of antibiotic associated nosocomial diarrhoea world-wide. Antibiotic therapy for an underlying condition disrupts the normal gut microflora and increases the risk of colonisation with C. difficile. The recent transcontinental spread of C. difficile hypervirulent lineages has been associated with high recurrence rates, increased levels of mortality and severe hospital outbreaks. Nevertheless, little is known about the mechanisms involved in colonisation of the gut and reactivation of disease. Current treatment regimes have varied efficacy and relapse rates are high, therefore C. difficile infection (CDI) remains a challenge to the healthcare industry. Lisa Dawson’s research interests are bacterial biofilms, which are recognised in other pathogens as vital for colonisation, persistence and virulence in a host. She has shown that C. difficile is capable of forming biofilms in-vitro and is interested in the mechanisms behind biofilm formation. C. difficile possesses a number of virulence traits; among them is the unique ability to produce para-cresol, a bacteriostatic phenolic agent. Lisa is currently involved in characterising the production of p-cresol by C. difficile and identifying the effect this has on modulation of the intestinal microbiome, Biofilm formed by C. difficile in-vitro using 16s rRNA sequencing. Selected publications 1. Cyclic-di-GMP regulates production of sortase substrates of Clostridium difficile and their surface exposure through ZmpI protease-mediated cleavage. Peltier J, et al. J Biol Chem 2015. 2. Clostridium difficile has a single sortase, SrtB, that can be inhibited by small-molecule inhibitors. Donahue EH, et al. BMC Microbiol 2014. 3. Clostridium difficile spo0A gene is a persistence and transmission factor. Deakin LJ, et al. Infect Immun 2012. 4. Characterisation of Clostridium difficile Biofilm Formation, a Role for Spo0A. Dawson LF, et al. PLoS One 2012. 5. The analysis of para-cresol production and tolerance in Clostridium difficile 027 and 012 strains. Dawson LF, et al. BMC Microbiol 2011.

http://www.lshtm.ac.uk/aboutus/people/dawson.lisa

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Nicholas Furnham Lecturer and MRC Methodology Research Fellow Nicholas Furnham’s research interests can be divided into gaining a fundamental understanding of the evolution of novel protein functions and the applications of the findings to important questions in infectious disease biology, in particular antimicrobial resistance and A the development of novel therapeutics. Using an interdisciplinary approach combining biology and chemistry with computer science his group develops new algorithms and bioinformatics tools through large-scale integrative data processing. Current research focuses on understanding the evolution of novel protein Afunctions and applying this B understanding to a diverse range of projects including: molecular consequences of genomic variance from GWAS studies in surveillance and tracking of antimicrobial resistance pharmacogenomics combined with high-content screening for drug repurposing in neglected tropical diseases putting allergy into its evolutionary context by IgE IgG establishing molecular similarities between known Predicting and testing IgE inducing allergens and proteins in multicellular parasites. Schistosoma worm

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Brich Pollen Schistosoma

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IgG ug/ml

1e+00 1e+00

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1e−01 1e−01



Brich Pollen Schistosoma

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

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

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betv1_ige0B betv1_ige0B

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Quality

epitopes in Schistosoma mansoni worms

Selected Publications: 1. Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity. Tyagi N, et al. PLoS Computational Biology 2015. 2. FunTree: advances in a resource for exploring and contextualising protein function evolution. Sillitoe I, et al. Nucleic Acids Res 2016. 3. Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. Phelan J, et al. BMC Medicine 2016. 4. Large-Scale Analysis Exploring Evolution of Catalytic Machineries and Mechanisms in Enzyme Superfamilies. Furnham N, et al. Journal Molecular Biology 2016. 5. EC-BLAST: a tool to automatically search and compare enzyme reactions. Rahman SA, et al. Nature Methods 2014.

http://www.lshtm.ac.uk/aboutus/people/furnham.nick

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IgE

I

Michael Gaunt Lecturer in Genome Parasitology The work focused on using evolutionary models to understand the molecular epidemiology or “microevolution” and “macroevolution” of the parasite Trypanosoma cruzi the causative agent of South American trypanosomiasis and its insect vector triatomine bugs. Microevolution: T. cruzi is a zoonose and the genetic relationship, or “population structure”, between sylvatic mammals and human reservoir hosts could have important public health implications. The team have developed a population genomics method using “microsatellite” genetic markers that provide the most accurate typing tool available for T. cruzi. The application of this tool to field isolates demonstrates T. cruzi has a complex epidemiology. For example, some ecotopes show a close genetic association between sylvatic hosts (rodents) and humans but other ecotopes (opossums) show a mixture of close and distant genetic associations. The microsatellites panel identified multiclonal infections as being much more important than previously thought. Macroevolution: Evolutionary studies on triatomine bugs revealed the insect evolved blood-feeding behaviour once and this occurred exactly at the same time as the formation of South America. Finally, theoretical work on evolutionary models reveals that several commonly used assumptions (mutation matrices) may result in erroneous epidemiological inferences. Refining these models provides new epidemiological insights. Selected publications 1. Recent, independent and anthropogenic origins of Trypanosoma cruzi hybrids. Lewis MD, et al. PLoS Negl Trop Dis 2011. 2. Phylogenetic multilocus codon models and molecular clocks reveal the monophyly of haematophagous reduviid bugs and their evolution at the formation of South America. Patterson P and Gaunt M, Mol Phyl Evol 2010. 3. Genome-scale multilocus microsatellite typing of Trypanosoma cruzi discrete typing unit I reveals phylogeographic structure and specific genotypes linked to human infection. Llewellyn M, et al. PLoS Pathog 2009. 4. Trypanosoma cruzi IIc: phylogenetic and phylogeographic insights from sequence and microsatellite analysis and potential impact on emergent Chagas disease. Llewellyn M, et al. PLoS Negl Trop Dis 2009.

www.lshtm.ac.uk/aboutus/people/gaunt.michael

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Esmeralda Valiente Lecturer in Molecular Microbiology Esmeralda Valiente was awarded a Marie Curie Intraeuropean Fellowship for career development. Esmeralda’s main interests include investigating new glycosylation systems in Clostridium difficile and various Vibrio species (in particular Vibrio cholerae O1 El Tor), and their potential role in bacterial virulence. Glycosylation is known to impart novel physical and biological roles to proteins in eukaryotes that can be grouped into two general categories, providing labels for protein recognition and for protein stabilization. In bacteria, protein glycosylation often has important roles in the survival and pathogenesis of bacteria and thus represent an ideal target to disable bacteria. Her studies were recently extended from C. difficile to Vibrio cholerae and other Vibrio species as part of a Wellcome Trust-funded collaboration with Professor Anne Dell’s group at Imperial College London. Esmeralda also collaborates with Professor Gordon Dougan and Nicholas Thompson at the Wellcome Trust Sanger Institute where Vibrio cholerae transcriptome and proteome analyses are conducted. Electron microscopy image of the bacterial pathogen Vibrio cholerae showing its polar flagellum.

Selected publications 1. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move. Valiente E, et al. Clin Microbiol and Infect 2014. 2. The post-translational modification of the Clostridium difficile flagellin affects motility, cell surface properties and virulence. Faulds-Pain A, et al. Mol Microbiol 2014. 3. Emergence of new PCR-ribotypes from the hypervirulent Clostridium difficile 027 lineage. Valiente E, et al. J. Med. Microbiol 2012. 4. Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Stabler RA, et al. Genome Biol 2009. 5. Role of the metalloprotease Vvp and the virulence plasmid pR99 of Vibrio vulnificus serovar E in surface colonization and fish virulence. Valiente E et al. Env. Microbiol 2008.

www.lshtm.ac.uk/aboutus/people/valiente.esmeralda

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