Asare Rexford, Kwaik Yousef Abu
Department of Microbiology and Immunology, School of Medicine, University of Louisville Louisville, KY, USA.
Front Microbiol. 2011 Jan 13;1:145. doi: 10.3389/fmicb.2010.00145. eCollection 2010.
Francisella tularensis is an intracellular bacterium that infects humans and many small mammals. During infection, F. tularensis replicates predominantly in macrophages but also proliferate in other cell types. Entry into host cells is mediate by various receptors. Complement-opsonized F. tularensis enters into macrophages by looping phagocytosis. Uptake is mediated in part by Syk, which may activate actin rearrangement in the phagocytic cup resulting in the engulfment of F. tularensis in a lipid raft rich phagosome. Inside the host cells, F. tularensis resides transiently in an acidified late endosome-like compartment before disruption of the phagosomal membrane and escape into the cytosol, where bacterial proliferation occurs. Modulation of phagosome biogenesis and escape into the cytosol is mediated by the Francisella pathogenicity island-encoded type VI-like secretion system. Whilst inside the phagosome, F. tularensis temporarily induce proinflammatory cytokines in PI3K/Akt-dependent manner, which is counteracted by the induction of SHIP that negatively regulates PI3K/Akt activation and promotes bacterial escape into the cytosol. Interestingly, F. tularensis subverts CD4 T cells-mediated killing by inhibiting antigen presentation by activated macrophages through ubiquitin-dependent degradation of MHC II molecules on activated macrophages. In the cytosol, F. tularensis is recognized by the host cell inflammasome, which is down-regulated by F. tularensis that also inhibits caspase-1 and ASC activity. During late stages of intracellular proliferation, caspase-3 is activated but apoptosis is delayed through activation of NF-κB and Ras, which ensures cell viability.
土拉弗朗西斯菌是一种胞内细菌，可感染人类和许多小型哺乳动物。在感染过程中，土拉弗朗西斯菌主要在巨噬细胞中复制，但也能在其他细胞类型中增殖。进入宿主细胞是由多种受体介导的。补体调理的土拉弗朗西斯菌通过环行吞噬作用进入巨噬细胞。摄取部分由Syk介导，Syk可能激活吞噬杯中的肌动蛋白重排，导致土拉弗朗西斯菌被富含脂筏的吞噬体吞噬。在宿主细胞内，土拉弗朗西斯菌短暂驻留在酸化的晚期内体样区室中，然后吞噬体膜破裂并逃逸到胞质溶胶中，细菌在胞质溶胶中发生增殖。吞噬体生物发生的调节和逃逸到胞质溶胶中是由弗朗西斯菌致病岛编码的VI型分泌系统介导的。在吞噬体内时，土拉弗朗西斯菌以PI3K/Akt依赖的方式暂时诱导促炎细胞因子，这被SHIP的诱导所抵消，SHIP负向调节PI3K/Akt激活并促进细菌逃逸到胞质溶胶中。有趣的是，土拉弗朗西斯菌通过泛素依赖的方式降解活化巨噬细胞上的MHC II分子，抑制活化巨噬细胞的抗原呈递，从而破坏CD4 T细胞介导的杀伤作用。在胞质溶胶中，土拉弗朗西斯菌被宿主细胞炎性小体识别，土拉弗朗西斯菌下调炎性小体，同时也抑制caspase-1和ASC的活性。在细胞内增殖的后期，caspase-3被激活，但通过激活NF-κB和Ras延迟细胞凋亡，从而确保细胞存活。
