Host Cell Responses To Salmonella Enterica Serovar Typhimurium

伤寒沙门氏菌是人和牛小肠结肠炎的常见原因，但在易感小鼠中会引起系统性伤寒样疾病。这种兼性细胞内病原体的发病机制依赖于侵袭非吞噬细胞的能力，如肠上皮中发现的那些细胞。侵袭依赖于III型分泌系统(T3SS1)，该系统用于将一组细菌效应蛋白转移到宿主细胞中。沙门氏菌在细胞内内化后，在一个修饰的吞噬小体--含沙门氏菌空泡(SCV)内存活和复制。第二个III型系统(T3SS2)是在细胞内诱导的，与SCV的细胞内生存/复制和生物发生有关。为了了解沙门氏菌的致病机制，我们必须剖析单独的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。寄主-病原体相互作用的另一个重要方面是SCV的生物发生。基于几个实验室的工作，人们普遍认为沙门氏菌阻止了SCV-溶酶体的融合，这是细胞内生存和复制的重要必要条件。我们已经证明，与这一教条相反，SCV的生物发生涉及与内吞途径的持续动态相互作用，包括晚期内小体和溶酶体。我们现在已经扩展了这项工作，以表明沙门氏菌诱导的小管，即众所周知的SIFs，是高度动态的，并表现出双向的、微管依赖的运动。此外，我们还证明了内体内容通过直接融合事件传递到Sifs。我们还发表了一项合作研究，揭示了毒力基因表达的新方面，特别是编码T3SS1和T3SS2的调节子。

Salmonella enterica serovar Typhimurium is a common cause of enterocolitis in humans and cattle but causes a systemic, typhoid-like, disease in susceptible mice. Pathogenesis of this facultative intracellular pathogen is dependent on the ability to invade non-phagocytic cells, such as those found in the intestinal epithelium. Invasion is dependent on a type III secretion system (T3SS1), which is used to translocate a set of bacterial effector proteins into the host cell. Following internalization intracellular Salmonella survive and replicate within a modified phagosome, the Salmonella-containing vacuole (SCV). A second type III system (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. A widely held belief, based on work from several labs, is that Salmonella prevent SCV-lysosome fusion and that this is an important requisite for intracellular survival and replication. We have shown that, contrary to this dogma, SCV biogenesis involves sustained dynamic interactions with the endocytic pathway including late endosomes and lysosome. We have now extended this work to show that Salmonella induced tubules, known as Sifs, are highly dynamic and exhibit bi-directional, microtubule-dependent movement. Furthermore, we demonstrated that endosomal content is delivered to Sifs by direct fusion events. We also published a collaborative study revealing new aspects of virulence gene expression, specifically of the regulons that encode T3SS1 and T3SS2.