Bacterial pathogenesis

Background

Hospital-acquired infections are presenting a major challenge to clinical practice and public health control. There is evidence that the modern hospital environment selects for super-fit variants of commensal, environmental or opportunistic pathogens that confound control and treatment regimens. The evolution and transmissibility of such organisms is tractable by high quality phylogenetic, phenotypic and epidemiological analysis.

Clostridium difficile is a prime example of a significant hospital-acquired pathogen. This bacterial species is a major cause of antibiotic-associated diarrhoea and is a rapidly emerging hospital-acquired infection currently confounding standard medical practices associated with antibiotic prescribing and infection control protocols. The use of antibiotics to treat other infections can trigger C. difficile disease and transmission, whereas antibiotics used to treat C. difficile infections are becoming less effective. Little is known about how C. difficile causes disease or transmits so efficiently within the hospital setting, but this appears to be due to an infective cycle that relies on highly resistant and infectious spores. An improved understanding of C. difficile biology, transmission and pathogenesis will directly benefit the ability to control and treat C. difficile in hospitals.

Research

The goals of the research programme are to investigate the genetic traits that contribute to C. difficile pathogenesis, persistence and transmission. Additional aims are to identify avenues for novel therapeutic intervention and to guide hospital infection control measures.

Collaborations

The Lawley Group has strong internal collaborations with the Microbial pathogenesis group, Pathogen Genomics Group, the Proteomic Mass Spectrometry Laboratory and the Mouse Genetics Programme.

The Group has several productive external collaborations including those with Professor Brendan Wren's Group at London School of Hygiene & Tropical Medicine (LSHTM) and Professor Neil Fairweather's Group at Imperial College London as well as close interactions with several NHS hospitals and the Health Protection Agency reference laboratories within the UK and abroad.

Selected Publications

• Evolutionary dynamics of Clostridium difficile over short and long time scales.

  He M, Sebaihia M, Lawley TD, Stabler RA, Dawson LF, Martin MJ, Holt KE, Seth-Smith HM, Quail MA, Rance R, Brooks K, Churcher C, Harris D, Bentley SD, Burrows C, Clark L, Corton C, Murray V, Rose G, Thurston S, van Tonder A, Walker D, Wren BW, Dougan G and Parkhill J

  Proceedings of the National Academy of Sciences of the United States of America2010;107;16;7527-32

  PUBMED: 20368420; PMC: 2867753; DOI: 10.1073/pnas.0914322107

• Antibiotic treatment of clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts.

  Lawley TD, Clare S, Walker AW, Goulding D, Stabler RA, Croucher N, Mastroeni P, Scott P, Raisen C, Mottram L, Fairweather NF, Wren BW, Parkhill J and Dougan G

  Infection and immunity2009;77;9;3661-9

  PUBMED: 19564382; PMC: 2737984; DOI: 10.1128/IAI.00558-09

• Proteomic and genomic characterization of highly infectious Clostridium difficile 630 spores.

  Lawley TD, Croucher NJ, Yu L, Clare S, Sebaihia M, Goulding D, Pickard DJ, Parkhill J, Choudhary J and Dougan G

  Journal of bacteriology2009;191;17;5377-86

  PUBMED: 19542279; PMC: 2725610; DOI: 10.1128/JB.00597-09

• Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium.

  Stabler RA, He M, Dawson L, Martin M, Valiente E, Corton C, Lawley TD, Sebaihia M, Quail MA, Rose G, Gerding DN, Gibert M, Popoff MR, Parkhill J, Dougan G and Wren BW

  Genome biology2009;10;9;R102

  PUBMED: 19781061; PMC: 2768977; DOI: 10.1186/gb-2009-10-9-r102

• Host transmission of Salmonella enterica serovar Typhimurium is controlled by virulence factors and indigenous intestinal microbiota.

  Lawley TD, Bouley DM, Hoy YE, Gerke C, Relman DA and Monack DM

  Infection and immunity2008;76;1;403-16

  PUBMED: 17967858; PMC: 2223630; DOI: 10.1128/IAI.01189-07

• Genome-wide screen for Salmonella genes required for long-term systemic infection of the mouse.

  Lawley TD, Chan K, Thompson LJ, Kim CC, Govoni GR and Monack DM

  PLoS pathogens2006;2;2;e11

  PUBMED: 16518469; PMC: 1383486; DOI: 10.1371/journal.ppat.0020011