Simonis Alexander, Hebling Sabrina, Gulbins Erich, Schneider-Schaulies Sibylle, Schubert-Unkmeir Alexandra
Institute of Hygiene and Microbiology, University of Wuerzburg, Wuerzburg, Germany.
Department of Molecular Medicine, University of Essen, Essen, Germany.
PLoS Pathog. 2014 Jun 12;10(6):e1004160. doi: 10.1371/journal.ppat.1004160. eCollection 2014 Jun.
The interaction with brain endothelial cells is central to the pathogenicity of Neisseria meningitidis infections. Here, we show that N. meningitidis causes transient activation of acid sphingomyelinase (ASM) followed by ceramide release in brain endothelial cells. In response to N. meningitidis infection, ASM and ceramide are displayed at the outer leaflet of the cell membrane and condense into large membrane platforms which also concentrate the ErbB2 receptor. The outer membrane protein Opc and phosphatidylcholine-specific phospholipase C that is activated upon binding of the pathogen to heparan sulfate proteoglycans, are required for N. meningitidis-mediated ASM activation. Pharmacologic or genetic ablation of ASM abrogated meningococcal internalization without affecting bacterial adherence. In accordance, the restricted invasiveness of a defined set of pathogenic isolates of the ST-11/ST-8 clonal complex into brain endothelial cells directly correlated with their restricted ability to induce ASM and ceramide release. In conclusion, ASM activation and ceramide release are essential for internalization of Opc-expressing meningococci into brain endothelial cells, and this segregates with invasiveness of N. meningitidis strains.
与脑内皮细胞的相互作用是脑膜炎奈瑟菌感染致病性的核心。在此，我们表明脑膜炎奈瑟菌会导致酸性鞘磷脂酶（ASM）短暂激活，随后脑内皮细胞中释放神经酰胺。响应脑膜炎奈瑟菌感染，ASM和神经酰胺在细胞膜外小叶展示，并凝聚成大的膜平台，该平台也会聚集表皮生长因子受体2（ErbB2）。病原体与硫酸乙酰肝素蛋白聚糖结合后被激活的外膜蛋白Opc和磷脂酰胆碱特异性磷脂酶C，是脑膜炎奈瑟菌介导的ASM激活所必需的。ASM的药理或基因消融消除了脑膜炎球菌的内化，而不影响细菌的黏附。相应地，ST-11/ST-8克隆复合体中一组特定致病分离株对脑内皮细胞的侵袭受限，这与其诱导ASM和神经酰胺释放的能力受限直接相关。总之，ASM激活和神经酰胺释放对于表达Opc的脑膜炎球菌内化入脑内皮细胞至关重要，并且这与脑膜炎奈瑟菌菌株的侵袭性相关。
