Université Paris Descartes, Faculté de Médecine, 75006 Paris, France.
Cell. 2010 Dec 23;143(7):1149-60. doi: 10.1016/j.cell.2010.11.035.
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.
脑膜炎奈瑟菌（N. meningitidis）是引起细菌性脑膜炎的细菌，它通过菌毛介导与人类脑内皮细胞黏附，启动信号级联反应，最终导致细胞间连接的开放，使脑膜得以定植。激活病原体的信号受体仍不清楚。我们报告称，脑膜炎奈瑟菌特异性地刺激内皮细胞中偏向性的β2-肾上腺素能受体/β-抑制蛋白信号通路，最终将β-抑制蛋白相互作用伙伴（如Src 酪氨酸激酶和连接蛋白）困住于细菌菌落下。β-抑制蛋白激活Src 介导的细胞骨架重排稳定了细菌与内皮细胞的黏附，而连接蛋白的β-抑制蛋白依赖性去定位导致细菌穿透组织的解剖间隙。用特异性激动剂激活β-肾上腺素能受体内吞作用可防止脑膜炎奈瑟菌黏附下游的信号事件，并抑制细菌穿过内皮屏障。劫持宿主细胞信号机制的机制的确定为脑膜炎奈瑟菌感染的治疗和预防开辟了新的前景。
