A Cellular Deficiency of Gangliosides Causes Hypersensitivity to Clostridium perfringens Phospholipase C

Clostridium perfringens phospholipase C (Cp-PLC), also called α-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 p...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-07, Vol.280 (29), p.26680-26689
Main Authors: Flores-Díaz, Marietta, Alape-Girón, Alberto, Clark, Graeme, Catimel, Bruno, Hirabayashi, Yoshio, Nice, Ed, Gutiérrez, José-María, Titball, Richard, Thelestam, Monica
Format: Article
Language:English
Subjects:
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
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Summary:Clostridium perfringens phospholipase C (Cp-PLC), also called α-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M500278200