Carneiro Leticia A M, Travassos Leonardo H, Soares Fraser, Tattoli Ivan, Magalhaes Joao G, Bozza Marcelo T, Plotkowski Maria C, Sansonetti Philippe J, Molkentin Jeffery D, Philpott Dana J, Girardin Stephen E
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Cell Host Microbe. 2009 Feb 19;5(2):123-36. doi: 10.1016/j.chom.2008.12.011.
Shigella rapidly kills myeloid cells via a caspase-1 inflammasome-dependent cell death mechanism. However, despite a critical role for nonmyeloid cells in the physiopathology of Shigella infection, the mechanism by which Shigella kills nonmyeloid cells remains uncharacterized. Here we demonstrate that, in nonmyeloid cells, Shigella infection induces loss of mitochondrial inner membrane potential, mitochondrial damage, and necrotic cell death through a pathway dependent on Bnip3 and cyclophilin D, two molecules implicated in the host oxidative stress responses. This mitochondrial cell death mechanism was potently counterbalanced by a Nod1-dependent Rip2/IKKbeta/NF-kappaB signaling pathway activated by the pathogen in the first hours of infection. Our results suggest that in nonmyeloid cells, oxidative stress pathways and signaling triggered by an intracellular bacterial pathogen are tightly linked and demonstrate the existence of specific Shigella-induced prodeath and prosurvival pathways converging at the mitochondria to control a necrotic cell death program.
志贺氏菌通过一种依赖半胱天冬酶-1炎性小体的细胞死亡机制迅速杀死髓样细胞。然而，尽管非髓样细胞在志贺氏菌感染的生理病理学中起关键作用，但志贺氏菌杀死非髓样细胞的机制仍未明确。在此，我们证明，在非髓样细胞中，志贺氏菌感染通过一条依赖Bnip3和亲环蛋白D的途径诱导线粒体内膜电位丧失、线粒体损伤和坏死性细胞死亡，这两种分子与宿主氧化应激反应有关。在感染的最初几个小时，病原体激活的一种依赖Nod1的Rip2/IKKβ/NF-κB信号通路有效地抵消了这种线粒体细胞死亡机制。我们的结果表明，在非髓样细胞中，细胞内细菌病原体触发的氧化应激途径和信号传导紧密相连，并证明存在特定的志贺氏菌诱导的促死亡和促存活途径，它们在线粒体处汇聚以控制坏死性细胞死亡程序。
