Abstract
Clostridium difficile infections can induce mild to severe diarrhoea and the often associated characteristic pseudomembranous colitis. Two protein toxins, the large glucosyltransferases TcdA and TcdB, are the main pathogenicity factors that can induce all clinical symptoms in animal models. The classical molecular mode of action of these homologous toxins is the inhibition of Rho GTPases by mono-glucosylation. Rho-inhibition leads to breakdown of the actin cytoskeleton, induces stress-activated and pro-inflammatory signaling and eventually results in apoptosis of the affected cells. An increasing number of reports, however, have documented further qualities of TcdA and TcdB, including the production of reactive oxygen species (ROS) by target cells. This review summarizes observations dealing with the production of ROS induced by TcdA and TcdB, dissects pathways that contribute to this phenomenon and speculates about ROS in mediating pathogenesis. In conclusion, ROS have to be considered as a discrete, glucosyltransferase-independent quality of at least TcdB, triggered by different mechanisms.
Highlights
C. difficile is a gram-positive anaerobic bacterium that causes antibiotic-associated diarrhoea and colitis
In addition to the major toxins, C. difficile produces a number of other putative virulence factors, e.g., the CDT binary toxin, which is produced in approximately 30% of all hypervirulent strains [6,7,8]
Cdc42 expression levels, but dependent on the presence of Rac1 [53]. These findings suggest a pathway in which Rac1 is involved in the recruitment and assembly of the NADPH oxidase (NOX) complex that is triggered by TcdB at high concentrations
Summary
C. difficile is a gram-positive anaerobic bacterium that causes antibiotic-associated diarrhoea and colitis. TcdA and TcdB are large (308 kDa and 270 kDa, respectively) glucosyltransferases that irreversibly inactivate Rho and Ras family GTPases, including Rho, Rac, Ras, Ral and Cdc, within the cell [2,3,4] Both toxins are responsible for massive fluid secretion, colonic tissue necrosis and inflammation associated with disease [5]. Inactivation of Rho GTPases induces a stress activated pro-inflammatory response such as up-regulation of interleukin-8, interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α) [28,29] Both toxins cause a cytopathic effect in cells, which is complete rounding of cells due to inhibition of Rho GTPases and reorganization of the actin cytoskeleton [30]. This review will focus on the newly discovered mechanism of cell death and the relevance of ROS production in TcdB-treated cells
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