Clostridium difficile Infection

The primary virulence factors that are known to cause clinical disease in Clostridium difficile infection (CDI) are the two large toxins: TcdA (toxin A; 308 kDa) and TcdB (toxin B; 270 kDa) ( 1 ). Both toxins are glucosyltransferases that inactivate Rho, Rac, and Cdc42 and result in actin condensation and subsequent cytoskeletal changes, apoptosis, and cell death of target cells. These toxins also induce an intense inflammatory response characterized by infiltration of inflammatory cells, especially neutrophils; activation of submucosal neurons; secretion of cytokines, chemokines, and arachidonic acid metabolites; and production of substance P and reactive oxygen intermediates ( 1 , 2 ). We have published previously that mediators of inflammation such as COX2 and angiotensin II, inflammatory cytokines such as interleukin-8 (IL-8), and immune cells such as neutrophils are significantly elevated in intestinal loops treated with TcdA ( 3 – 5 ). Similarly, we see in our patients’ histopathology mucosal disruption, intense inflammatory cell infiltration, and thick fibrinous exudates of degenerating cells (pseudomembranes), which are the hallmarks of pseudomembranous colitis (PMC) ( 6 ) ( Fig. 1 ). Increased fecal lactoferrin, IL-1β, and IL-8 were observed in patients with CDI ( 7 ). The link between glucosylation of the small GTPases and induction of the inflammatory cascade is unclear. This raises the possibility that the host inflammatory response is not a direct effect of the toxins on intracellular signaling but a concerted response by the cells surrounding the “intoxicated” cell to the changes that occurred in the latter.