title: A cellular deficiency of gangliosides causes hypersensitivity to Clostridium perfringens phospholipase C.
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.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm S-17177, Sweden.
authors.forename: Marietta
authors.initials: M
authors.lastname: Flores-Díaz
authors.forename: Alberto
authors.initials: A
authors.lastname: Alape-Girón
authors.forename: Graeme
authors.initials: G
authors.lastname: Clark
authors.forename: Bruno
authors.initials: B
authors.lastname: Catimel
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Ed
authors.initials: E
authors.lastname: Nice
authors.forename: José-María
authors.initials: JM
authors.lastname: Gutiérrez
authors.forename: Richard
authors.initials: R
authors.lastname: Titball
authors.forename: Monica
authors.initials: M
authors.lastname: Thelestam
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D003016:Clostridium perfringens / Q000201:enzymology / Q000276:immunology* / Q000472:pathogenicity; D004357:Drug Synergism; D005732:Gangliosides / Q000172:deficiency* / Q000502:physiology; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology*; D008081:Liposomes; D051379:Mice; D009439:Neuraminidase / Q000008:administration & dosage / Q000494:pharmacology; D012794:Sialic Acids; D010738:Type C Phospholipases / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology
chemical_list: D005732:Gangliosides; D008081:Liposomes; D012794:Sialic Acids; D010738:Type C Phospholipases; D009439:Neuraminidase