Hathaway Lucy J, Griffin George E, Sansonetti Philippe J, Edgeworth Jonathan D
Department of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom.
Infect Immun. 2002 Jul;70(7):3833-42. doi: 10.1128/IAI.70.7.3833-3842.2002.
Shigella flexneri infection of human macrophages is followed by rapid bacterial escape into the cytosol and secretion of IpaB, which activates caspase-1 to mediate cell death and release of mature interleukin (IL)-1 beta. Here we report a different outcome following infection of human peripheral blood monocytes. S. flexneri infects monocytes inefficiently in the absence of complement and, following complement-dependent uptake, cannot escape the endosomal compartment. Consequently, bacteria are killed within the first 60 min in the absence of monocyte cell death, as demonstrated by immunofluorescence and electron microscopy and enumeration of colonies in a gentamicin protection assay. Despite early bacterial death, wild-type S. flexneri influenced the subsequent monocyte proinflammatory cytokine response and cell fate. Infection with wild-type S. flexneri resulted in IpaB-dependent suppression of IL-1 beta, tumor necrosis factor alpha, and IL-6 compared with that of plasmid-cured avirulent S. flexneri-infected cells. Furthermore, over the following 6 to 8 h, virulent S. flexneri-infected monocytes died by apoptosis whereas avirulent infected monocytes died by necrosis. Together, these results imply that monocytes migrating into the inflammatory site during the early stages of shigellosis kill S. flexneri but that during bacterial uptake, they receive virulence signals from S. flexneri which induce delayed apoptosis associated with suppression of the proinflammatory cytokine response to bacterial phagocytosis. This delayed apoptosis may have important effects on the ordered initiation of the innate immune response, leading to the excessive inflammatory response characteristic of shigellosis.
福氏志贺菌感染人类巨噬细胞后,细菌会迅速逃逸到细胞质中并分泌IpaB,IpaB可激活半胱天冬酶-1以介导细胞死亡并释放成熟的白细胞介素(IL)-1β。在此,我们报告了人类外周血单核细胞感染后的不同结果。在没有补体的情况下,福氏志贺菌对单核细胞的感染效率低下,并且在补体依赖性摄取后,无法从内体区室逃逸。因此,如免疫荧光、电子显微镜以及庆大霉素保护试验中的菌落计数所示,在没有单核细胞死亡的情况下,细菌会在最初60分钟内被杀死。尽管细菌早期死亡,但野生型福氏志贺菌影响了随后单核细胞的促炎细胞因子反应和细胞命运。与质粒消除的无毒福氏志贺菌感染的细胞相比,野生型福氏志贺菌感染导致IL-1β、肿瘤坏死因子α和IL-6受到IpaB依赖性抑制。此外,在接下来的6至8小时内,有毒力的福氏志贺菌感染的单核细胞通过凋亡死亡,而无毒力感染的单核细胞则通过坏死死亡。总之,这些结果表明,在志贺菌病早期迁移到炎症部位的单核细胞会杀死福氏志贺菌,但在细菌摄取过程中,它们会从福氏志贺菌接收毒力信号,这些信号会诱导与抑制对细菌吞噬作用的促炎细胞因子反应相关的延迟凋亡。这种延迟凋亡可能对先天免疫反应的有序启动具有重要影响,导致志贺菌病特有的过度炎症反应。