Cytosolic Immune Surveillance During Bacterial Infections

 描述（由申请人提供）：脓毒症是一种高度致命的综合征，每年影响美国120多万人和全球1800万人。更好地了解潜在的免疫机制是非常需要开发具体和有效的药物。先天免疫系统是感知入侵病原体和激活宿主免疫反应的中心。一组不同的生殖系编码的先天免疫受体调查几乎所有的细胞区室的病原体及其产物的存在。炎性小体是细胞溶质中的多蛋白支架，其含有NLR受体、衔接子ASC和效应子胱天蛋白酶-1。炎性小体是细胞质免疫监视的组成部分。炎性小体直接检测各种“标志性”微生物产物或间接感知与感染相关的体征。尽管革兰氏阴性菌的脂多糖（LPS）被认为仅在细胞表面被Toll样受体-4（TLR 4）检测到，但最近已经描述了LPS在胞质溶胶中以TLR 4非依赖性方式被caspase-11（一种炎性caspase）感知。细胞内LPS激活caspase-11，导致caspase-1蛋白水解激活，然后执行IL-1β和IL-18的激活。重要的是，活性胱天蛋白酶-11触发细胞死亡的炎性形式（焦亡）和内源性警报素或危险分子的释放，使炎性反应永久化。脂多糖的胞浆感受和随后的半胱天冬酶-11活化是脓毒症的中心介质。尽管其深刻的临床意义，该途径的机制的细节，关于LPS的胞质进入的分子基础和下游信号级联的调节仍然在很大程度上是未知的。本研究旨在全面解决这些关键的知识差距在三个具体目标。目标1和2将确定LPS如何进入细胞溶质并激活caspase-11，目标3将表征在小鼠和人类中保持炎症性caspase介导的免疫应答的调节机制。通过揭示人类细胞溶质LPS传感驱动反应的分子细节，这项研究的发现可以提供新的免疫调节策略和靶点，以加强保护性免疫，并阻断感染性疾病中所需的有害炎症。

 DESCRIPTION (provided by applicant): Sepsis is a highly lethal syndrome that affects more than 1.2 million people in the Unites States and 18 million globally each year. A better understanding of the underlying immune mechanisms is greatly needed to develop specific and effective drugs. Innate immune system is central to the sensing of invading pathogens and the activation of the host immune response. A diverse set of germ-line encoded innate immune receptors survey nearly all-cellular compartments for the presence of pathogens and their products. Inflammasomes are multi- protein scaffolds in the cytosol containing a NLR receptor, an adapter ASC, and an effector, caspase-1. Inflammasome is an integral part of the immunosurveillance of the cytosol. Inflammasomes directly detect various "signature" microbial products or indirectly sense signs associated with an infection. Although lipopolysaccharide (LPS) of Gram-negative bacteria was believed to be exclusively detected at the cell surface by Toll-like receptor-4 (TLR4), it has very recently been described that the LPS is sensed in the cytosol in a TLR4-independent manner by caspase-11, an inflammatory caspase. Activation of caspase-11 by intracellular LPS leads to the proteolytic activation of caspase-1, which then executes the activation of IL-1β and IL-18. Importantly, active caspase-11 triggers an inflammatory form of cell death (pyroptosis) and the release of endogenous alarmin or danger molecules that perpetuate the inflammatory reactions. Cytosolic sensing of LPS and the ensuing caspase-11 activation is the central mediator of sepsis. Despite its profound clinical implications the mechanistic details of this pathway regarding the molecular basis of cytosolic entry of LPS and the regulation of the downstream signaling cascade remains largely unknown. This study seeks to comprehensively address these critical knowledge gaps in three specific aims. Aim 1 and 2 will identify how LPS enters the cytosol and activates caspase-11 and Aim 3 will characterize a regulatory mechanism that keeps inflammatory caspases-mediated immune responses in check in mice and humans. By uncovering the molecular details of cytosolic LPS sensing-driven responses in humans, the findings from this study could offer new immunomodulatory strategies and targets to bolster protective immunity as well as block detrimental inflammation as desired in infectious diseases.