Mechanisms of Inflammasome Inhibition by Salmonella

描述（由申请人提供）：本项目的长期目标是了解细菌病原体如何逃避宿主先天免疫应答，并认为这将有助于深入了解宿主-病原体相互作用并促进抗菌治疗的开发。肠道沙门氏菌感染诱导免疫细胞的快速募集和肠道炎症。沙门氏菌能够存活，甚至利用这种炎症反应全身传播。相反，全身性感染，特别是在慢性阶段，与明显高水平的宿主炎症无关。该提议的一个关键基础假设是沙门氏菌通过调节宿主炎症反应促进持续感染。细菌感染的天然免疫识别涉及模式识别受体，其感测保守的微生物结构以及毒力活性。胞质Nod样受体（NLR）蛋白家族的成员响应于检测到胞质中的微生物产物或微生物毒力因子对细胞膜的破坏而直接组装称为“炎性体”的多蛋白复合物。炎性小体组装诱导半胱天冬酶-1的活化、半胱天冬酶-1依赖性裂解和IL-1家族细胞因子的分泌以及半胱天冬酶-1依赖性促炎性细胞死亡（焦亡）。炎性小体激活在宿主防御多种病原体中起关键作用，但最近发现许多细菌和病毒病原体干扰炎性小体激活。沙门氏菌对炎性小体的激活涉及通过NLRC 4感测细菌鞭毛蛋白，以及通过NLRP 3感测未知细菌信号。沙门氏菌下调鞭毛蛋白表达以逃避NLRC 4炎性体，但沙门氏菌如何阻止NLRP 3炎性体激活尚不清楚。我们已经使用了一种新的筛选方法，以确定沙门氏菌基因调节NLRP 3炎性小体激活。由于在该筛选中鉴定的许多基因有助于沙门氏菌的持久性，我们的中心假设是逃避炎性小体激活促进沙门氏菌的持久性。本项目的目标1将确定我们已经鉴定的沙门氏菌基因的NLRP 3炎性小体逃避的机制。本项目的目的2将测试炎性小体逃避在建立和维持沙门氏菌持续感染中的作用。这些研究将为沙门氏菌-宿主相互作用的关键方面提供新的见解，并可能提供新的治疗靶点。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how bacterial pathogens evade host innate immune responses with the view that this will provide insight into host-pathogen interactions and facilitate development of antimicrobial therapeutics. Salmonella infection of the intestine induces rapid recruitment of immune cells and intestinal inflammation. Salmonella is able to survive and even takes advantage of this inflammatory response to spread systemically. In contrast, systemic infection, particularly during the chronic stage, is not associated with overtly high levels of host inflammation. A key underlying hypothesis of this proposal is that Salmonella promotes persistent infection by modulating host inflammatory responses. Innate immune recognition of bacterial infection involves pattern recognition receptors that sense conserved microbial structures as well as virulence activities. Members of the cytosolic Nod-like Receptor (NLR) protein family direct assembly of multiprotein complexes termed 'inflammasomes' in response to detection of microbial products in the cytosol or disruption of cellular membranes by microbial virulence factors. Inflammasome assembly induces activation of caspase-1, and caspase-1 dependent cleavage and secretion of IL-1 family cytokines and a caspase-1 dependent pro-inflammatory cell death (pyroptosis). Inflammasome activation plays a key role in host defense against diverse pathogens, but a number of bacterial and viral pathogens have recently been found to interfere with inflammasome activation. Activation of inflammasomes by Salmonella involves sensing of bacterial flagellin by NLRC4, and sensing of an unknown bacterial signal by NLRP3. Salmonella downregulates flagellin expression to evade the NLRC4 inflammasome, but how Salmonella might prevent NLRP3 inflammasome activation is not known. We have used a novel screening approach to identify Salmonella genes that modulate NLRP3 inflammasome activation. As a number of genes identified in this screen contribute to Salmonella persistence, our central hypothesis is that evading inflammasome activation promotes Salmonella persistence. Aim 1 of this project will define the mechanisms of NLRP3 inflammasome evasion by the Salmonella genes we have identified. Aim 2 of this project will test the role of inflammasome evasion in establishing and maintaining Salmonella persistent infection. These studies will provide novel insight into a critical aspect of Salmonella-host interactions, and are likely to provide novel therapeutic targets.