Invasion and intracellular replication of Salmonella Typhimurium in epithelial cells

鼠伤寒沙门氏菌是人和牛小肠结肠炎的常见病因，但在易感小鼠中会引起一种系统性的伤寒样疾病。这种兼性的细胞内病原体入侵非吞噬细胞，如在肠道上皮中发现的细胞，并在一个被称为含沙门氏菌空泡(SCV)的改良吞噬小体中生存。两个III型分泌系统(T3SS)将不同的细菌效应蛋白转移到宿主细胞中，是建立细胞内复制环境所必需的。侵袭依赖于T3SS1，而T3SS2是在细胞内诱导的，并与SCV的细胞内生存/复制和生物发生有关。最近，我们一直在研究上皮细胞中空泡复制和胞浆复制的相对重要性。在大约5%-20%的感染细胞中，鼠伤寒沙门氏菌从液泡中逃逸，并在胞浆中存活和复制。我们已经发现，这些胞质细菌触发了一个非规范的caspase4/11炎症体反应，这对于肠道上皮的抗菌防御是重要的。目前，我们正在完成的一项研究表明，在以后的时间点上，T3SS1在胞质细菌中具有功能活性，而T3SS2仅在空泡细菌中具有功能活性。

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a common cause of enterocolitis in humans and cattle but causes a systemic, typhoid-like, disease in susceptible mice. This facultative intracellular pathogen invades non-phagocytic cells, such as those found in the intestinal epithelium, and survives within a modified phagosome known as the Salmonella-containing vacuoles (SCV). Two type III secretion systems (T3SS), which translocate distinct cohorts of bacterial effector proteins into the host cell, are required for establishment of the intracellular replicative environment. Invasion is dependent on T3SS1 whereas T3SS2 is induced intracellularly and is associated with intracellular survival/replication and biogenesis of the SCV. Recently we have been investigating the relative importance of vacuolar versus cytosolic replication in epithelial cells. In approximately 5-20% of infected cells S. Typhimurium escape from the vacuole and survive and replicate in the cytosol. We have found that these cytosolic bacteria trigger a non canonical caspase 4/11 inflammasome response that is important for antimicrobial defense in the intestinal epithelium. Currently we are completing a study showing that at later time points the T3SS1 is functionally active in the cytosolic bacteria whereas the T3SS2 is functionally active only in the vacuolar bacteria.