Infectious Diseases: Clostridium difficile infection (CDI)

Clostridium difficile infection (CDI) causes antibiotic associated diarrhea and pseudomemberous colitis, mostly in the elderly and in hospitalized patients. The main cause of pathology is colonic expression of two large glucosylating toxins, TcdA and TcdB. Research in the Department of Infectious Diseases and Global Health aims to understand the mechanisms of toxin-mediated inflammation and to investigate the role of each toxin in the pathogenesis of C. difficile-associated diseases. The Department is developing CDI models in the gnotobiotic pig model transplanted with the human microbiome and generating recombinant CDI vaccines. In addition, we are evaluating antimicrobial agents and immune-based therapies, including separately, the Merck and the MedImmune human monoclonal antibodies and hyperimmune bovine colostrum, to treat and/or prevent CDI disease. We are also advancing development of single-domain antibodies (sdAbs) derived from alpacas, called VHHs, that target and neutralize the C. difficile toxins, TcdA and TcdB. The VHHs are engineered into heteromultimers resulting in potent antitoxin VHH-based neutralizing agents (VNAs) that have demonstrated efficacy in mouse and pig models of CDI when administered as proteins or by gene therapy. More details on VNAs are available at the Novel Antitoxin Agents webpage. More recently we have embarked on attempting to define the precise role of each of the CDI virulence factors contributing to diarrhea, mucosal lesions and to systemic disease, using a panel of 6 isogenic mutants expressing a single virulence factor. We are also attempting to understand why monoclonal antibody directed against TcdA exasperate the clinical symptoms rather than provide protection against the toxin in pigs and in humans.

Publications

Research in the Department of Infectious Diseases and Global Health aims to understand the mechanisms of toxin-mediated inflammation and to investigate the role of each toxin in the pathogenesis of C. difficile-associated diseases.