Surface layer proteins of Clostridium difficile as novel vaccine candidates

THESIS 8529Clostridium difficile is a major cause of antibiotic associated diarrhoea and pseudomembranous colitis in hospitalised patients. The major precipitating factor for C. difficile-associated disease (CDAD) is disruption of the normal gut flora by antibiotic therapy. C. difficile can then colonise the gut and produce the toxins, which mediate much of its pathogenesis. Currently, there is no C. difficile vaccine licensed for human use. A toxin-based vaccine is under development and has shown promise. However, this vaccine will not prevent colonisation and thus transmission is likely to remain a problem. C. difficile expresses two major surface layer proteins (SLPs), the low-molecular weight (MW) SLP and the high-MW SLP, which form a crystalline regular array on its outer surface. A single gene, slpA, encodes a precursor protein which is processed to remove a signal peptide and then undergoes a second cleavage to release the two mature SLPs. The low-MW SLP exhibits a high degree of inter-strain variability and can elicit a serum antibody response in infected individuals. The high-MW SLP is putatively involved in gut colonisation. The SLPs, therefore, represent good novel targets for vaccine development against C. difficile. This study was chiefly concerned with the generation of strong immune responses against the SLPs with a view to developing a vaccine against C. difficile