Genetic and phenotypic characterisation of emerging virulent Clostridium difficile. (360G-Wellcome-086418_Z_08_Z)

The current epidemic of C. difficile-associated disease has been accompanied predominantly by the emergence of two clonal groups of 027 and A-B+ strains that are associated with increased disease severity. We recently compared genome sequence data from historical non-epidemic and contemporary epidemic 027 and A-B+ strains and identified several genetic regions of difference that could explain the emergence of the epidemic phenotype. In parallel studies, assays have identified significant pheno typic differences between non- epidemic and epidemic 027 strains. In this study we will determine the genetic and phenotypic attributes that could explain the emergence of epidemic strains. This will include the rigorous characterization of epidemic strains and respective mutants using relevant in vitro and in vivo assays. In complementary studies, comparative phylogenomics, MLST analysis and SNP typing will be used to establish an evolutionary framework for C. difficile strains. This analysis wi ll help to (i) determine the distribution of newly found virulence determinants, (ii) trace the origin of 027 and A-B+ strains and (iii) predict the emergence of further epidemic clones. The two lineages of epidemic C. difficile provide a unique opportunity to study the recent emergence of hypervirulent bacteria and improve our general understanding of the evolution of bacterial virulence