A cellular deficiency of gangliosides causes hypersensitivity to Clostridium perfringens phospholipase C
Fecha
2005-07-22
Tipo
artículo original
Autores
Flores Díaz, Marietta
Alape Girón, Alberto
Clark, Graeme
Catimel, Bruno
Hirabayashi, Yoshio
Nice, Ed
Gutiérrez, José María
Titball, Richard
Thelestam, Mónica
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Resumen
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.
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Palabras clave
Animals, Cell Line, Cell Membrane, Clostridium Perfringens, Drug Synergism, Gangliosides, Humans, Hypersensitivity, Liposomes, Mice, Neuraminidase, Sialic Acids, Type C Phospholipases