Clostridium difficile is a spore-forming bacterium that is the leading cause of antibiotic-associated diarrhea (CDAD) and is a problematic hospital-acquired pathogen. Despite the fact that patients are infected via ingestion of the spores yet only the vegetative form of C. difficile can produce the toxins that result in the pathological effects of CDAD, the molecular basis of germination of C. difficile spores in the intestinal mucosal environment has not been examined. Through our prior work with Vibrio cholerae, we have developed a simple, flexible, and effective ex vivo model that recapitulates the conditions found in the mammalian intestine, representing a major new tool in the study of intestinal pathogens that promises to pave the way for developing virulence-targeted drugs and vaccines. This model will be used to determine the rate of germination of spores as well as aid in the identification of host- or bacterial flora-derived signals that induce germination. In addition, the ex vivo model will be used to identify genes induced upon germination using a genetic screen. Identification of signals that affect spore germination and knowledge of how genes are regulated during germination may provide potential therapeutic targets for blocking C. difficile infection. Once spores have germinated into vegetative cells, it is not known how they evade the host immune system. Our preliminary data indicate that cells grown in vitro, but not those grown in the presence of intestinal tissues, can bind to the mucosal antibody, secretory IgA. The immune evasion strategies employed by C. difficile will be examined, including whether C. difficile modulates the expression of its surface proteins in response to the host environment and what host signal is responsible for this. In addition, the consequences of S-lgA binding to C. difficile will be examined, including the fate of cells bound to S-lgA and possible avoidance strategies used by C. difficile. Identification of immunogenic cell surface factors and/or understanding the mechanisms of immune evasion could lead to novel treatment options for CDAD.
As CDAD is a major and growing problem in hospital settings, new strategies for combating this disease are needed. Our studies will provide a broader understanding of the bacteria-host interactions that allow C. difficile to be a successful pathogen, with the ultimate goal of discovering novel treatment options for CDAD.
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