title: Reactive Oxygen Species as Additional Determinants for Cytotoxicity of Clostridium difficile Toxins A and B.
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.
authors.affiliation: Postgraduate Course for Toxicology and Environmental Toxicology, Institute for Legal Medicine, University of Leipzig, Johannisallee 28, Leipzig 04103, Germany. fraedrich_claudia@hotmail.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Frädrich
authors.affiliation: Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany. beer.lara-antonia@mh-hannover.de.
authors.forename: Lara-Antonia
authors.initials: LA
authors.lastname: Beer
authors.affiliation: Postgraduate Course for Toxicology and Environmental Toxicology, Institute for Legal Medicine, University of Leipzig, Johannisallee 28, Leipzig 04103, Germany. Gerhard.ralf@mh-hannover.de.|Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany. Gerhard.ralf@mh-hannover.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gerhard
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D016923:Cell Death; D004768:Enterotoxins / Q000633:toxicity*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D017382:Reactive Oxygen Species; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile
keywords: Clostridium difficile infection; NADPH oxidase; Rho GTPases; cytotoxicity; neutrophils; reactive oxygen species; toxin