title: New insights into the cytotoxic mechanisms of Clostridium perfringens enterotoxin.
abstract: Clostridium perfringens type A isolates producing the 35 kDa enterotoxin (CPE) are an important cause of food poisoning, human non-foodborne gastrointestinal (GI) disease, and some veterinary GI diseases. Studies using CPE knock-out mutants confirmed the importance of enterotoxin expression for the enteric virulence of CPE-positive type A isolates. CPE action involves formation of a series of complexes in mammalian plasma membranes. One such CPE-containing complex (of approximately 155 kDa) is important for the induction of plasma membrane permeability alterations, which are responsible for killing enterotoxin-treated mammalian cells. Those membrane permeability changes damage the epithelium, allowing the enterotoxin to interact with the tight junction (TJ) protein occludin. CPE:occludin interactions result in formation of an approximately 200 kDa CPE complex and internalization of occludin into the cytoplasm. That removal of occludin (and possibly other proteins) damages TJs and disrupts the normal paracellular permeability barrier of the intestinal epithelium, which may contribute to CPE-induced diarrhea. Recent studies demonstrated that low CPE doses kill mammalian cells by inducing a classic apoptotic pathway involving mitochondrial membrane depolarization, cytochrome C release, and caspase 3/7 activation. In contrast, high enterotoxin doses induce oncosis, a proinflammatory event. Thus, inflammation may also contribute to the GI symptoms of patients whose intestines contain high CPE levels. In summary, CPE is a unique, multifunctional toxin with cytotoxic, TJ-damaging, and (probably) proinflammatory activities.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. bamcc@pitt.edu
authors.forename: Bruce A
authors.initials: BA
authors.lastname: McClane
authors.forename: Ganes
authors.initials: G
authors.lastname: Chakrabarti