Microbial pathogenesis

The Microbial pathogenesis team, under the leadership of Gordon Dougan, is focusing on the genetic analysis of the interactions between bacteria and their hosts to shed light on how humans and other animals respond to infection.

This information will be exploited towards developing methods of controlling infection, including vaccines and antibiotics, in the continuing fight against disease that is crucial for populations worldwide.

The team is also investigating the relationships between different members of the family of bacteria that cause typhoid, Salmonella Typhi, in order to explain their evolution, antibiotic resistance and transmission within the human population.

Finally the team is involved in a number of major high profile collaborations worldwide investigating methods for developing vaccines against typhoid, dysentery, malaria, and tuberculosis, all critically important diseases particularly in the third world.

[David Goulding, Genome Research Limited]

Background

Infectious diseases still pose a threat at a global and local level, particularly as disease agents can evolve so quickly. For example, bacteria such as Salmonella and Shigella cause intestinal infections that can have devastating consequences particularly in third world countries, but bacterial strains such as these can be resistant to almost all antibiotics.

New approaches are needed to treat bacterial infections, one of which is focusing on understanding the methods by which the body's natural systems fight off the tens of thousands of potentially pathogenic bacteria to which it is exposed in ordinary everyday life.

A complementary challenge is investigating how disease agents change to prevent human intervention? Understanding the molecular basis of infection could assist in attempts to develop vaccines and other therapies to protect against infections.

Research

Our aims

The Microbial pathogenesis team is dedicated to understanding the fundamental interactions that occur between the host - i.e. the infected human or mouse - and the pathogen; and also to understanding the evolution of members of the families of the pathogen that causes typhoid and how this affects transmission of the disease in human populations. We use genetics as a core tool, studying both the host and the pathogen.

Figure 1. Images of pathogenic bacteria interacting with the gut.

Figure 1. Images of pathogenic bacteria interacting with the gut. [David Goulding, Genome Research Limited]

Our approach

We are running an integrated research programme that uses a variety of genetic approaches to study host-pathogen interactions. We are also undertaking a detailed molecular analysis of microbial populations through a faculty research programme, as well as providing significant support to Pathogen genomics (formerly the PSU) and the Mouse genetics programme.

Faculty Programme (Deputy Head, Dr Robert Kingsley)

We are focusing our research around the biology of intestinal bacterial infections, with a strong emphasis on invasive Salmonella disease and Clostridium difficile (a sub-project headed by Dr Trevor Lawley). We are working closely with Pathogen Genomics and have generated information on the genome sequences of a number of different Salmonella species or serovars including Bongori, Typhi, Typhimurium, Enteritidis, Gallinarum, Hadar, Infantis, Senftenberg and Paratyphi A that cause potentially lethal diseases such as typhoid and salmonella food poisoning. We have also determined the phylogenetic structure of C. difficile. We are using the information to investigate, at the genetic level, what makes different species of bacteria more potent (or virulent), in terms of their ability to cause disease, than others. To complement this research we are creating 'libraries' of pathogen strains that have single genes disabled in order to investigate their (the genes') functions and effects on virulence.

We are also undertaking an analysis of microbial population structure in collaboration with Dr Mark Achtman at the Max Planck Institute for Infection Biology, Berlin, and Dr Jeremy Farrar at the Wellcome Unit in Ho Chi Minh City. We are concentrating efforts on Salmonella typhi, which causes typhoid, and C. difficile, a common cause of infection in hospitals but have projects on other pathogens including Vibrio cholerae. We use DNA sequencing and gene-functionality based approaches, and exploit this information for biological experimentation. Another key study involves the analysis of the genome of S. typhimurium, responsible for invasive bacterial disease throughout Africa. This is run in collaboration with Dr Sam Kariuki in Nairobi and the Wellcome Unit in Blantyre, Malawi.

Mouse genetic infection susceptibility programme (Deputy Head, Dr Simon Clare)

We run a component of the mouse genetic programme in which mice with an artificially disabled gene are challenged with certain pathogens. The aim is to identify mammalian genes that contribute to controlling susceptibility to infection. The main infectious agents used in this screen are currently S. typhimurium and Citrobacter rodentium, although other pathogens can be exploited to investigate genetic effects in detail.

Other methods exploited to investigate infections

The Microbial pathogenesis team also runs state-of-the-art fluorescence activated cell sorting (FACS) and microscopy suites. The microscopy/imaging facility, run by David Goulding, provides access to wide-field, confocal and electron microscopes (EM) and auxiliary equipment for specimen processing. The facility has expertise in transmission and scanning EM techniques and specialises in cryopreservation for immunoEM including high pressure freezing, freeze-substitution and ultrathin sectioning of hydrated specimens for immunogold-localisation. The prep lab also supports routine processing of specimens for chemical fixation, epon embedding, ultrathin sectioning, rotary shadowing and carbon-coating.

Our vaccine work and other key collaborations

We are collaborating in research into mucosal vaccines - i.e. vaccines that work at the point of entry of the pathogens that cause HIV and tuberculosis - in a project called MUVAPRED, which is funded by the EU. We are also working on understanding the genetics of innate immunity in a project called Innate Pathogenomics funded by Genome Canada, and Novel Therapeutics that boost Innate Immunity to treat Infectious Diseases funded through the Grand Challenges in Global Health (GCGH) initiative by the Foundation for National Institutes of Health (FNIH) and also by the Canadian Institutes for Health Research (CIHR).

Other collaborative projects include investigations into Clostridium difficile E coli infections with our collaborator Dr Gad Frankel based at Imperial College London, bacteriophage analysis through our collaborator Dr George Salmond at Cambridge University and Shigella/Vibrio cholerae through links with the International Vaccine Institute in Korea.

Selected Publications

  • The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children.

    MacLennan CA, Gondwe EN, Msefula CL, Kingsley RA, Thomson NR, White SA, Goodall M, Pickard DJ, Graham SM, Dougan G, Hart CA, Molyneux ME and Drayson MT

    The Journal of clinical investigation 2008;118;4;1553-62

  • A linear plasmid truncation induces unidirectional flagellar phase change in H:z66 positive Salmonella Typhi.

    Baker S, Holt K, Whitehead S, Goodhead I, Perkins T, Stocker B, Hardy J and Dougan G

    Molecular microbiology 2007;66;5;1207-18

  • Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.

    Stecher B, Robbiani R, Walker AW, Westendorf AM, Barthel M, Kremer M, Chaffron S, Macpherson AJ, Buer J, Parkhill J, Dougan G, von Mering C and Hardt WD

    PLoS biology 2007;5;10;2177-89

  • Requirement of bic/microRNA-155 for normal immune function.

    Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M and Bradley A

    Science (New York, N.Y.) 2007;316;5824;608-11

Team

No team members listed

* quick link - http://q.sanger.ac.uk/micrpath