The Salmonella-Containing Vacuole

肠炎沙门氏菌血清型鼠伤寒沙门氏菌是人类和牛肠道结肠炎的常见病因，但在易感小鼠中引起系统性伤寒样疾病。这种同时性细胞内病原体侵入非吞噬细胞，如在肠上皮中发现的细胞，并在被称为含沙门氏菌液泡（SCV）的改良吞噬体中存活。两种III型分泌系统（T3SS）将不同的细菌效应蛋白转运到宿主细胞中，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，与细胞内存活/复制和SCV的生物发生有关。为了了解沙门氏菌的发病机制，我们必须剖析单个T3SS1和T3SS2效应蛋白的作用，以及控制它们在宿主细胞内表达和活性的机制。宿主-病原体相互作用的另一个重要方面是SCV的生物发生，从最初的形成到最终的细菌释放。我们之前已经表明，SCV的生物发生涉及与内吞途径（包括晚期内体和溶酶体）的持续动态相互作用。我们现在的工作重点是SCV形成的初始阶段，目标是获得膜褶和新生吞噬体的详细蛋白质组学数据。在这些组分中富集的宿主细胞蛋白将被跟踪以确定它们在这一过程中的作用。

Salmonella enterica serovar 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. To understand Salmonella pathogenesis we must dissect the roles of the individual T3SS1 and T3SS2 effector proteins as well as the mechanisms that control their expression and activity inside host cells. Another important aspect of the host-pathogen interaction is the biogenesis of the SCV, from initial formation through to the ultimate release of bacteria. We have previously shown that SCV biogenesis involves sustained dynamic interactions with the endocytic pathway including late endosomes and lysosome. We are now focusing our efforts on the initial stages of SCV formation, with the goal of obtaining detailed proteomics data on the membrane ruffles and nascent phagosome. Host cell proteins enriched in these fractions will be followed up to establish their roles in the process.