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J. Biol. Chem., Vol. 280, Issue 29, 26680-26689, July 22, 2005

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

Marietta Flores-Díaz, Alberto Alape-Girón¶||, Graeme Clark**, Bruno Catimel, Yoshio Hirabayashi, Ed Nice, José-María Gutiérrez, Richard Titball**, and Monica Thelestam

From the Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm S-17177, Sweden, Instituto Clodomiro Picado, Facultad de Microbiología, and ^¶Departamento de Bioquímica, Facultad de Medicina, Universidad de Costa Rica, San José, 2060 Costa Rica, ^**Defence Science and Technology Laboratory, Porton Down, Salisbury, Wilts SP4 0JQ, United Kingdom, Ludwig Institute for Cancer Research, P.O. Royal Melbourne Hospital, Parkville, Melbourne, Victoria 3050, Australia, and Institute of Physical and Chemical Research (RIKEN) 2-1 Hirosawa, Wako-shi, Saitama 351-01, Japan

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

Received for publication, January 10, 2005 , and in revised form, May 26, 2005.

^* This work was supported by Costa Rica-United States Foundation Grant CT13-02, Swedish Cancer Society Grant 3826-B96-01XAB, Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Vicerrectoria de Investigación, Universidad de Costa Rica Grants 741-98-287, 741-A0-510, and 741-A3-503, Swedish Research Council Grant 16X-05969, and Karolinska Institutet Research Funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, 2060 San José, Costa Rica. Tel.: 506-2290344 or 506-2293135; Fax: 506-2920485; E-mail: aalape{at}cariari.ucr.ac.cr.

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