REGULATORY MECHANISMS CONTROLLING TCDE PRODUCTION IN CLOSTRIDIUM DIFFICILE

Project SummaryClostridium difficile, a major nosocomial pathogen is the principal causative agent of antibiotic associateddiarrhea and pseudomembranous colitis. The toxigenic C. difficile strains that cause disease secrete virulencefactors, toxin A and toxin B, which are responsible for colonic injury and inflammation. C. difficile toxins haveno export signature and are secreted by an unusual mechanism that involves TcdE, a holin-like protein. Likeother channel forming proteins, TcdE exists as the oligomer in C. difficile membrane. The preliminary studyfound tcdE mRNA to contain multiple start-codons that translate into three different isoforms. It was also notedthat tcdE over-expression in bacteria causes membrane damage. Based on these observations, it washypothesized that TcdE content in C. difficile is highly controlled through various regulatory mechanisms. Aim 1of this application will determine how transcription of a tcdE gene is regulated and will also study the regulatorymechanisms involved in the translation control of tcdE mRNA into different TcdE isoforms. Aim 2 will determinethe importance of TcdE in C. diffcile pathogenesis by employing the well standardized C. difficile hamsterinfection model. Since TcdE has a prominent role in toxin secretion, this study can help us to understand thetoxin secretion mechanism and its significance in C. difficile pathogenesis.