Role of Clostridium perfringens phospholipase C in the pathogenesis of gas gangrene

Abstract

Gas gangrene is an acute and devastating infection most frequently caused by Clostridium perfringens and characterized by severe myonecrosis, intravascular leukocyte accumulation, and significant thrombosis. Several lines of evidence indicate that C. perfringens phospholipase C (Cp-PLC), also called alpha-toxin, is the major virulence factor in this disease. This toxin is a Zn 2+ metalloenzyme with lecithinase and sphingomyelinase activities. Its three dimensional structure shows two domains, an N-terminal domain which contains the active site, and a C-terminal domain required for the Ca 2+dependent interaction with membranes. Cp-PLC displays several biological activities: it increases capillary permeability, induces platelet aggregation, hemolysis, myonecrosis, decreases cardiac contractility, and is lethal. Experiments with genetically engineered Cp-PLC variants have revealed that the sphingomyelinase activity and the C-terminal domain are required for toxicity. The myotoxicity of Cp-PLC is largely dependent on its membrane damaging effect. In addition, it has been suggested that the alterations in the blood flow induced by this toxin also contribute to muscle damage. In gas gangrene, Cp-PLC dysregulates transduction pathways in endothelial cells, platelets and neutrophils leading to the uncontrolled production of several intercellular mediators and adhesion molecules. Thus, Cp-PLC alters the traffic of neutrophils to the infected tissue and promotes thrombotic events, enhancing the conditions for anaerobic growth.