BROAD BACKGROUND & LONG-TERM GOAL

Clostridium difficile, an etiologic agent for pseudomembranous colitis, accounts for a quarter cases of antibiotic-associated diarrhea. With the recent emergence of hypervirulent strains, the incidence of C. difficile infection (CDI) has increased significantly in both North America and Europe, causing lengthy hospitalization, substantial morbidity and mortality. CDI is thought to be mainly mediated by exotoxins TcdA and TcdB, which glucosylate low molecular mass GTPase of the Rho family, leading to massive fluid secretion, acute inflammation, and necrosis of the colonic mucosa.

Our long-term goal is to understand the mechanisms mediating intestinal inflammation in C. difficile infection and to utilize this knowledge for the design of better immune interventions in order to reduce the incidence of CDI and severity of the disease. The interaction of intestinal epithelial cells (IECs) with intestinal antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages, in the gut orchestrates mucosal immune homeostasis and inflammatory response. Our objective is to elucidate the immune response of IECs and intestinal DCs after their exposure to C. difficile toxins and to determine the nature of their interaction on initiating intestinal inflammation and tissue destruction.

WORKING HYPOTHESES

1. C. difficile toxin-intoxicated IECs are capable of mobilizing and activating DCs;
2. In severe cases of CDI, C. difficile toxins can cross a severely damaged intestinal barrier and further activate DCs and macrophages;
3. proinflammatory cytokine TNF-a synergizes with the toxins to induce apoptosis of IECs, thus exacerbating tissue destruction and enterocolitis.

By testing these hypotheses, we expect to gain a better understanding of not only the underlying mechanisms by which C. difficile toxins induce severe enterocolitis, but also the role of IEC-DC interaction in the onset and development of intestinal inflammatory diseases in general. We believe that such an understanding will help us to design better immune interventions against CDI and other intestinal inflammatory diseases.

PUBLIC HEALTH RELEVANCE And GOAL

Clostridium difficile is the most common cause of hospital-acquired antibiotic-associated diarrhea and the etiologic agent of pseudomembranous colitis, the most severe intestinal inflammation. The diseases are mainly caused by toxins secreted by the bacteria. The goal of this project is to elucidate the immune response of the intestinal epithelial cells (the first line of cells encountering the toxins) and intestinal dendritic cells (the immune cells regulating intestinal inflammatory response) after their exposure to C. difficile toxins and to determine the nature of their interaction on initiating intestinal inflammation and tissue destruction. We believe the study will help us to design better immune interventions against C. difficile infection and other intestinal inflammatory diseases.