Abstract
Clostridium difficile is a major cause of nosocomial diarrhea, with 30-day mortality reaching 30%. The cell surface comprises a paracrystalline proteinaceous S-layer encoded by the slpA gene within the cell wall protein (cwp) gene cluster. Our purpose was to understand the diversity and evolution of slpA and nearby genes also encoding immunodominant cell surface antigens. Whole-genome sequences were determined for 57 C. difficile isolates representative of the population structure and different clinical phenotypes. Phylogenetic analyses were performed on their genomic region (>63 kb) spanning the cwp cluster. Genetic diversity across the cwp cluster peaked within slpA, cwp66 (adhesin), and secA2 (secretory translocase). These genes formed a 10-kb cassette, of which 12 divergent variants were found. Homologous recombination involving this cassette caused it to associate randomly with genotype. One cassette contained a novel insertion (length, approximately 24 kb) that resembled S-layer glycosylation gene clusters. Genetic exchange of S-layer cassettes parallels polysaccharide capsular switching in other species. Both cause major antigenic shifts, while the remainder of the genome is unchanged. C. difficile genotype is therefore not predictive of antigenic type. S-layer switching and immune escape could help explain temporal and geographic variation in C. difficile epidemiology and may inform genotyping and vaccination strategies.
| Original language | English |
|---|---|
| Pages (from-to) | 675-686 |
| Number of pages | 12 |
| Journal | Unknown Journal |
| Volume | 207 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 15 Feb 2013 |
Bibliographical note
Funding Information:Acknowledgments. We thank the staff of the Clinical Microbiology Laboratory and Infection Control, John Radcliffe Hospital, Oxford, and the staff of the Infection Control Laboratory staff, Leeds General Infirmary, for their assistance throughout this work. This publication made use of the Clostridium difficile Multilocus Sequence Typing Web site (available at: http://pubmlst.org/cdifficile/sited) at the Department of Zoology, University of Oxford. The development of this Web site has been funded by the Wellcome Trust.
Funding Information:
Financial support. This work was supported by the Oxford NIHR Biomedical Research Centre (Senior Investigator Award to T. E. P. and D. W. C. and doctoral research fellowship to D. W. E.); by the UKCRC Modernising Medical Microbiology Consortium, which is funded under the UKCRC Translational Infection Research Initiative and supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, and the National Institute for Health Research on behalf of the United Kingdom Department of Health (grant G0800778) and The Wellcome Trust (grant 087646/Z/08/Z); and by the Engineering and Physical Sciences Research Council (to M. A. A.).
