Clostridium difficile and Clostridium sordellii toxins, proinflammatory versus anti-inflammatory response

Clostridium difficile and Clostridium sordellii produce related potent toxins (C. difficile toxin A (TcdA) and toxin B (TcdB), C. sordellii lethal toxin (TcsL) and hemorrhagic toxin (TcsH)) which belong to the large clostridial glucosylating toxin (LCGT) family. TcsL is the main C. sordellii toxin as most of toxigenic C. sordellii strains only synthesize this toxin. Intestinal colonization by C. difficile subsequently to unbalanced microbiota is accompanied by release of toxins which induce local tissue destruction and severe inflammatory response. TcdA and TcdB inactivate Rho-GTPases. Notably inactivation of RhoA results in the stimulation of the pyrin/ASC inflammasome, which is one of the main signaling pathways used by these toxins to trigger the inflammatory response. In contrast, TcsL induces an anti-inflammatory effect, mainly by inactivating Ras proteins which results in blockage of the cell cycle and killing of immune cells. The absence or moderate local inflammatory response allows C. sordellii spreading in deep tissues, production of toxin which is released in the general circulation and causes a toxic shock syndrome. The toxin mechanisms of pro-versus anti-inflammatory responses are discussed.