A cellular deficiency of gangliosides causes hypersensitivity to Clostridium perfringens phospholipase C

J Biol Chem. 2005 Jul 22;280(29):26680-9. doi: 10.1074/jbc.M500278200. Epub 2005 May 26.

Abstract

Clostridium perfringens phospholipase C (Cp-PLC), also called alpha-toxin, is the major virulence factor in the pathogenesis of gas gangrene. Previously, a cellular UDP-Glc deficiency was related with a hypersensitivity to the cytotoxic effect of Cp-PLC. Because UDP-Glc is required in the synthesis of proteoglycans, N-linked glycoproteins, and glycosphingolipids, the role of these gly-coconjugates in the cellular sensitivity to Cp-PLC was studied. The cellular sensitivity to Cp-PLC was significantly enhanced by glycosphingolipid synthesis inhibitors, and a mutant cell line deficient in gangliosides was found to be hypersensitive to Cp-PLC. Gangliosides protected hypersensitive cells from the cytotoxic effect of Cp-PLC and prevented its membrane-disrupting effect on artificial membranes. Removal of sialic acids by C. perfringens sialidase increases the sensitivity of cultured cells to Cp-PLC and intramuscular co-injection of C. perfringens sialidase, and Cp-PLC in mice potentiates the myotoxic effect of the latter. This work demonstrated that a reduction in gangliosides renders cells more susceptible to the membrane damage caused by Cp-PLC and revealed a previously unrecognized synergism between Cp-PLC and C. perfringens sialidase, providing new insights toward understanding the pathogenesis of clostridial myonecrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / drug effects
  • Clostridium perfringens / enzymology
  • Clostridium perfringens / immunology*
  • Clostridium perfringens / pathogenicity
  • Drug Synergism
  • Gangliosides / deficiency*
  • Gangliosides / physiology
  • Humans
  • Hypersensitivity / etiology*
  • Liposomes
  • Mice
  • Neuraminidase / administration & dosage
  • Neuraminidase / pharmacology
  • Sialic Acids
  • Type C Phospholipases / administration & dosage
  • Type C Phospholipases / immunology*
  • Type C Phospholipases / pharmacology

Substances

  • Gangliosides
  • Liposomes
  • Sialic Acids
  • Type C Phospholipases
  • Neuraminidase