A cellular deficiency of gangliosides causes hypersensitivity to Clostridium perfringens phospholipase C
A cellular deficiency of gangliosides causes hypersensitivity to Clostridium perfringens phospholipase C
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DOI：
10.1074/jbc.m500278200
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发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Titball, R
中科院分区：
文献类型：
--
作者：
Flores-Díaz, M;Alape-Girón, A;Titball, R
产气荚膜梭菌磷脂酶C（ClostridiumperfringensphospholipaseC，Cp-PLC）又称α毒素，是气性坏疽的主要致病因子。以前，细胞UDP-Glc缺陷与对Cp-PLC的细胞毒性作用的超敏反应有关。由于UDP-Glc是合成蛋白聚糖、N-连接糖蛋白和鞘糖脂所必需的，因此研究了这些糖缀合物在细胞对Cp-PLC敏感性中的作用。细胞对Cp-PLC的敏感性显着增强的鞘糖脂合成抑制剂，和神经节苷脂缺乏的突变细胞系被发现对Cp-PLC过敏。神经节苷脂保护过敏细胞免受Cp-PLC的细胞毒性作用，并防止其对人工膜的膜破坏作用。C.去除唾液酸产气荚膜杆菌唾液酸酶增加培养细胞对Cp-PLC和肌内共注射C.小鼠中的产气荚膜杆菌唾液酸酶和Cp-PLC增强了后者的肌毒作用。这项工作表明，神经节苷脂的减少使细胞更容易受到Cp-PLC引起的膜损伤，并揭示了Cp-PLC和C之间以前未被认识到的协同作用。产气荚膜梭菌唾液酸酶，为了解梭菌肌坏死的发病机制提供了新的见解。
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 glycoconjugates 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.