Clostridium difficile is a Gram positive, spore-forming rod that causes a spectrum of intestinal diseases extending from relatively mild diarrhea to toxic megacolon and is a frequent cause of hospital-acquired enteric infection. C. difficile associated disease (CDAD) generally occurs in hospitalized patients and almost always follows antibiotic treatment for unrelated infections. The incidence of CDAD has increased in the United States, from less than 150,000 cases in 2000 to an estimated 500,000 cases in 2006, with approximately 15,000 to 20,000 deaths. As such, C. difficile colitis has become one of the most important and expensive health-care associated infections. Recurrence rates after treatment are high (Figure 1). The role of the immune system in defense against this infection or in the pathogenesis of C. difficile-associated disease is poorly defined.
Treatment of mice with broad spectrum antibiotics renders mice susceptible to infection with Clostridium difficile and causes destruction of the epithelial barrier in the cecum and colon and edema of the underlying lamina propria and bowel wall.
We are investigating a murine model of antibiotic-induced C. difficile colitis and are focusing on novel approaches to ameliorate infection and to decrease the intestinal pathology associated with CDAD. We find that flagellin treatment markedly increases survival of mice infected with C. difficile. Ongoing studies in the laboratory are determining the range of TLR agonists that can enhance resistance to C. difficile infection. Our overall goal is to identify approaches to prevent the development of CDAD and to characterize the mechanisms by which TLR ligands and the normal intestinal microbiota prevent the development of CDAD.