Salmonella typhimurium invasion induces apoptosis in infected macrophages.

Invasive Salmonella typhimurium induces dramatic cytoskeletal changes on the membrane surface of mammalian epithelial cells and RAW264.7 macrophages as part of its entry mechanism. Noninvasive S. typhimurium strains are unable to induce this membrane ruffling. Invasive S. typhimurium strains invade RAW264.7 macrophages in 2 h with 7- to 10-fold higher levels than noninvasive strains. Invasive S. typhimurium and Salmonella typhi, independent of their ability to replicate intracellularly, are cytotoxic to RAW264.7 macrophages and, to a greater degree, to murine bone marrow-derived macrophages. Here, we show that the macrophage cytotoxicity mediated by invasive Salmonella is apoptosis, as shown by nuclear morphology, cytoplasmic vacuolization, and host cell DNA fragmentation. S. typhimurium that enter cells causing ruffles but are mutant for subsequent intracellular replication also initiate host cell apoptosis. Mutant S. typhimurium that are incapable of inducing host cell membrane ruffling fail to induce apoptosis. The activation state of the macrophage plays a significant role in the response of macrophages to Salmonella invasion, perhaps indicating that the signal or receptor for initiating programmed cell death is upregulated in activated macrophages. The ability of Salmonella to promote apoptosis may be important for the initiation of infection, bacterial survival, and escape of the host immune response. IMAGES:

侵袭性鼠伤寒沙门氏菌（Salmonella typhimurium）作为其入侵机制的组成部分，可诱导哺乳动物上皮细胞与RAW264.7巨噬细胞（RAW264.7 macrophages）的细胞膜表面发生显著的细胞骨架改变。非侵袭性鼠伤寒沙门氏菌菌株无法诱导此类膜褶皱现象。侵袭性鼠伤寒沙门氏菌菌株可在2小时内侵袭RAW264.7巨噬细胞，其侵袭水平是非侵袭性菌株的7至10倍。侵袭性鼠伤寒沙门氏菌与伤寒沙门氏菌（Salmonella typhi），无论其胞内复制能力如何，均对RAW264.7巨噬细胞具有细胞毒性，且对小鼠骨髓来源巨噬细胞的细胞毒性更为显著。本研究证实，侵袭性沙门氏菌介导的巨噬细胞毒性属于细胞凋亡（apoptosis），该结论可通过细胞核形态、胞质空泡化以及宿主细胞DNA片段化得到验证。能够侵入细胞并引发膜褶皱，但后续胞内复制存在缺陷的鼠伤寒沙门氏菌突变株，同样可启动宿主细胞凋亡；而无法诱导宿主细胞膜褶皱的鼠伤寒沙门氏菌突变株，则无法引发细胞凋亡。巨噬细胞的激活状态对巨噬细胞应对沙门氏菌入侵的反应具有显著影响，这提示激活的巨噬细胞中，启动程序性细胞死亡的信号或受体表达可能发生了上调。沙门氏菌促进细胞凋亡的能力，可能对感染起始、细菌存活以及逃逸宿主免疫应答具有重要意义。图像：