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Host Cell Responses To Salmonella Enterica Serovar Typhimurium

宿主细胞对肠沙门氏菌鼠伤寒血清型的反应

基本信息

批准号：
7732572
负责人：
Olivia Steele-Mortimer
金额：
$ 145.44万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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.

鼠伤寒沙门氏菌是人类和牛小肠结肠炎的常见病因，但在易感小鼠中引起全身性伤寒样疾病。这种兼性细胞内病原体的发病机制依赖于侵入非吞噬细胞的能力，例如在肠上皮中发现的那些。入侵依赖于III型分泌系统（T3 SS 1），其用于将一组细菌效应蛋白易位到宿主细胞中。在内化后，细胞内沙门氏菌存活并在修饰的吞噬体（含沙门氏菌的空泡（SCV））内复制。第二种III型系统（T3 SS 2）在细胞内诱导，并且与SCV的细胞内存活/复制和生物发生相关。为了了解沙门氏菌的发病机制，我们必须剖析T3 SS 1和T3 SS 2效应蛋白的作用，以及控制它们在宿主细胞内的表达和活性的机制。宿主-病原体相互作用的另一个重要方面是SCV的生物发生。基于几个实验室的工作，人们普遍认为沙门氏菌阻止了SCV-溶酶体融合，这是细胞内存活和复制的重要条件。我们已经表明，与这一教条相反，SCV生物发生涉及持续的动态相互作用与内吞途径，包括晚期内体和溶酶体。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（称为Sifs）是高度动态的，并表现出双向的微管依赖性运动。此外，我们证明了内体内容物通过直接融合事件递送到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T3 SS 1和T3 SS 2的调节子。