Clostridium difficile toxins: mediators of inflammation

Clostridium difficile is a significant problem in hospital settings as the most common cause of nosocomial diarrhea worldwide. C. difficile infections (CDIs) are characterized by an acute intestinal inflammatory response with neutrophil infiltration. These symptoms are primarily caused by the glucosylating toxins, TcdA and TcdB. In the past decade, the frequency and severity of CDIs have increased markedly due to the emergence of so-called hypervirulent strains that overproduce cytotoxic glucosylating toxins relative to historical strains. In addition, these strains produce a third toxin, binary toxin or C. difficile transferase (CDT), that may contribute to hypervirulence. Both the glucosylating toxins and CDT covalently modify target cell proteins to cause disassembly of the actin cytoskeleton and induce severe inflammation. This review summarizes our current knowledge of the mechanisms by which glucosylating toxins and CDT disrupt target cell function, alter host physiology and stimulate immune responses.