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

Marietta Flores-Diaz, Alberto Alape-Giron, Graeme Clark, Bruno Catimel, Yoshio Hirabayashi, Edouard C Nice, Jose-Maria Gutierrez, Richard Titball, Monica Thelestam

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46 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)26680 - 26689
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number29
Publication statusPublished - 2005
Externally publishedYes

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