The Clostridium difficile S-layer in infection and transmission (360G-Wellcome-204877_Z_16_Z)

The surface exposed, semi-rigid proteinaceous S-layer of Clostridium difficile has been linked to several key pathogenicity traits including colonisation and activation of inflammatory immune responses. Recent isolation and characterisation of a spontaneous S-layer mutant has revealed an inability of this strain to initiate fatal disease in the hamster model and severe sporulation defects. These observations infer a pivotal role in infection and transmission, which requires further investigation to provide greater molecular understanding of the role of the S-layer in C. difficile disease. Isolation of this strain, and the availability of the molecular tools to allow manipulation of SlpA, the major protein of the S-layer, provide a unique opportunity to determine the fundamental role of this structure in disease. We will combine our joint expertise to unravel the molecular details of S-layer structure and function, including its link to effective sporulation, transmission and specific role in infection. Further, the opportunity to express 13 previously identified clinically relevant variants of this protein within a single strain, will allow definitive conclusions regarding the specific role of SlpA in colonisation, immune activation and disease severity. Such information is crucial to our understanding of C. difficile biology and the future development of effective therapeutics.