Cytosolic Immune Surveillance During Bacterial Infections

细菌感染期间的细胞质免疫监视

• 批准号: 9225153
• 负责人: Vijay Rathinam
• 金额: $ 39.52万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225153
• 关键词: Address; Affect; Attenuated; Autophagocytosis; Bacteria; Bacterial Infections; CASP1 gene; Caring; Caspase; Cell Death; Cell Fractionation; Cell membrane; Cell physiology; Cell surface; Cells; Clinical; Communicable Diseases; Cytosol; Data; Death Rate; Detection; Disease; Endocytosis; Escherichia coli; Gene Expression Regulation; Germ Lines; Goals; Gram-Negative Bacteria; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunologic Receptors; Immunologic Surveillance; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-18; Invaded; Knowledge; Lectin; Life; Lipopolysaccharides; Lipoprotein Receptor; Mediating; Mediator of activation protein; Membrane; Microscopic; Molecular; Mus; Orthologous Gene; Outcome; Pathogenesis; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Play; Reaction; Regulation; Role; Safety; Sepsis; Septic Shock; Severities; Signal Transduction; Surveys; Syndrome; TLR4 gene; Testing; Transcriptional Regulation; United States; Vaccines; Vesicle; Virulence Factors; Work; base; clinical development; cost; defense response; extracellular; immune activation; immunoregulation; improved; in vivo; insight; microbial; mortality; mutant; oxidized low density lipoprotein; pathogen; public health relevance; receptor; response; scaffold; scavenger receptor

 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.

 描述（由申请人提供）：败血症是一种高度致命的综合症，每年影响美国超过 120 万人，全球超过 1800 万人。开发特异性有效的药物非常需要更好地了解潜在的免疫机制。先天免疫系统对于感知入侵病原体和激活宿主免疫反应至关重要。一组不同的种系编码的先天免疫受体调查几乎所有细胞区室中是否存在病原体及其产物。炎症小体是细胞质中的多蛋白支架，含有 NLR 受体、接头 ASC 和效应子 caspase-1。炎症小体是细胞质免疫监视的一个组成部分。炎性体直接检测各种“特征”微生物产物或间接感知与感染相关的体征。尽管人们认为革兰氏阴性细菌的脂多糖 (LPS) 在细胞表面仅由 Toll 样受体 4 (TLR4) 检测到，但最近有报道称 LPS 在胞质溶胶中被 caspase-11（一种炎症性 caspase）以不依赖于 TLR4 的方式感知。细胞内 LPS 激活 caspase-11 导致 caspase-1 蛋白水解激活，然后激活 IL-1β 和 IL-18。重要的是，活性 caspase-11 会引发炎症形式的细胞死亡（细胞焦亡），并释放内源性警报素或危险分子，从而使炎症反应持续下去。 LPS 的胞质传感和随后的 caspase-11 激活是脓毒症的核心介质。尽管其具有深远的临床意义，但该途径有关 LPS 进入胞质的分子基础和下游信号级联的调节的机制细节仍然很大程度上未知。本研究旨在通过三个具体目标全面解决这些关键知识差距。目标 1 和 2 将确定 LPS 如何进入细胞质并激活 caspase-11，目标 3 将描述一种调节机制，以控制小鼠和人类中炎症性 caspase 介导的免疫反应。通过揭示人类细胞质 LPS 传感驱动反应的分子细节，这项研究的结果可以提供新的免疫调节策略和目标，以增强保护性免疫并阻止传染病所需的有害炎症。