法国发现脑膜炎病菌致病机制

　　法国国家科研中心12月23日发表公报说，该机构同法国国家健康与医学研究所合作，发现了脑膜炎病菌的致病机制。这一成果将有助于开发预防脑膜炎的新药。

　　公报说，脑膜炎双球菌在刚刚侵入患者喉部时不会导致任何症状，但它会随着血液循环进入大脑，并突破毛细血管壁，引起脑膜炎发作。

　　研究人员发现，为了侵入大脑，该细菌采取“两步走”策略：首先，它会向大脑毛细血管的内皮细胞发出信号，使其生成芽状物，帮助自己在流动的血液中“站稳脚跟”。随后，它再设法破坏细胞膜的密闭性，让一些接合处产生松动，从而进入大脑毛细血管的内皮细胞。在此过程中，患者体内的β2－肾上腺素能受体发挥了重要作用，脑膜炎双球菌依靠它的帮助，促使维系细胞膜密闭性的蛋白质丧失稳定性，从而达到传播脑膜炎的目的。

　　脑膜炎可由细菌和病毒等引起，其中由脑膜炎双球菌引起的流行性脑膜炎是最严重的脑膜炎之一，多发于婴幼儿和青少年。如果治疗不及时，患者可能会在数小时内死亡或造成永久性脑损伤。

　　研究人员认为，如能使用药物对β2－肾上腺素能受体进行控制，将有望预防双球菌引起的脑膜炎。该研究成果已发表在最新一期美国《细胞》杂志上。

　　推荐原文出处：

　　Cell   doi:10.1016/j.cell.2010.11.035

　　Meningococcus Hijacks a β2-Adrenoceptor/β-Arrestin Pathway to Cross Brain Microvasculature Endothelium

　　Authors

　　Mathieu Coureuil, Hervé Lécuyer, Mark G.H. Scott, Cédric Boularan, Hervé Enslen, Magali Soyer, Guillain Mikaty, Sandrine Bourdoulous, Xavier Nassif, Stefano Marullo

　　Highlights

　　Meningococci interact with and activate brain endothelial cell β2-adrenoceptors

　　Receptor-recruited β-arrestins activate Src and delocalize cell-junction proteins

　　Bacterial colonies require β-arrestins for stable adhesion and to cross endothelium

　　Agonist-induced endocytosis of β2-adrenoceptors prevents bacterial signaling

　　Summary

　　Following pilus-mediated adhesion to human brain endothelial cells, meningococcus (N. meningitidis), the bacterium causing cerebrospinal meningitis, initiates signaling cascades, which eventually result in the opening of intercellular junctions, allowing meningeal colonization. The signaling receptor activated by the pathogen remained unknown. We report that N. meningitidis specifically stimulates a biased β2-adrenoceptor/β-arrestin signaling pathway in endothelial cells, which ultimately traps β-arrestin-interacting partners, such as the Src tyrosine kinase and junctional proteins, under bacterial colonies. Cytoskeletal reorganization mediated by β-arrestin-activated Src stabilizes bacterial adhesion to endothelial cells, whereas β-arrestin-dependent delocalization of junctional proteins results in anatomical gaps used by bacteria to penetrate into tissues. Activation of β-adrenoceptor endocytosis with specific agonists prevents signaling events downstream of N. meningitidis adhesion and inhibits bacterial crossing of the endothelial barrier. The identification of the mechanism used for hijacking host cell signaling machineries opens perspectives for treatment and prevention of meningococcal infection.