Molecular Mechanisms of Inflammasome Activation During Salmonella Infections

描述（由申请人提供）：我们研究沙门氏菌与宿主的相互作用，并表明哺乳动物炎症小体，一种介导促炎宿主反应的先天免疫保护复合物，对控制鼠伤寒沙门氏菌感染很重要。本研究应用的长期目标是了解宿主如何识别细胞内鼠伤寒沙门氏菌，以及这种病原体如何进化以破坏先天免疫防御。我们已经证明，多个宿主细胞质传感器参与识别胞内鼠伤寒沙门氏菌和激活炎性体。此外，我们已经表明，在细胞内鼠伤寒沙门氏菌的反应中形成了多个caspase-1复合物。在Aim1中，我们将使用遗传和生化方法来识别参与caspase- 1依赖性成熟和促炎细胞因子释放的新宿主分子和途径。在Aim 2中，我们将采用生化和遗传学方法来鉴定参与caspase-1诱导的巨噬细胞死亡的宿主分子和途径。在Aim 3中，我们将描述caspase-1复合物形成、细胞因子释放和宿主细胞死亡之间的时空关系。这些研究旨在更好地了解细胞内识别的分子机制，这将导致合理设计治疗方法，从而有利于公众健康。

DESCRIPTION (provided by applicant): We study Salmonella-host interactions and have shown that the mammalian inflammasome, an innate immune protective complex that mediates a pro-inflammatory host response, is important for controlling S. typhimurium infection. The long-term goal of this research application is to understand how the host recognizes intracellular S. typhimurium and how this pathogen has evolved to subvert innate immune defenses. We have demonstrated that multiple host cytosolic sensors are involved in recognizing intracellular S. typhimurium and activating the inflammasome. In addition, we have shown that multiple caspase-1 complexes are formed in response to intracellular S. typhimurium. In Aim1, we will use genetic and biochemical approaches to identify new host molecules and pathways involved in caspase- 1-dependent maturation and release of pro-inflammatory cytokines. In Aim 2, we will take biochemical and genetic approaches to identify host molecules and pathways involved in caspase-1-induced macrophage death. In Aim 3, we will characterize the spatial and temporal relationships between caspase-1 complex formation, cytokine release and host cell death. These studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular recognition, which will lead to the rational design of therapeutics that will benefit public health.