Article

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

Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm S-17177, Sweden.
Journal of Biological Chemistry (impact factor: 4.77). 08/2005; 280(29):26680-9. DOI:10.1074/jbc.M500278200 pp.26680-9
Source: PubMed

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.

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Keywords

artificial membranes
 
C. perfringens sialidase
 
C. perfringens sialidase increases
 
cellular UDP-Glc deficiency
 
clostridial myonecrosis
 
Clostridium perfringens phospholipase C
 
cytotoxic effect
 
gangliosides renders cells
 
gas gangrene
 
glycosphingolipid synthesis inhibitors
 
intramuscular co-injection
 
major virulence factor
 
membrane damage
 
membrane-disrupting effect
 
mutant cell line deficient
 
myotoxic effect
 
N-linked glycoproteins
 
new insights
 
sialic acids
 
unrecognized synergism