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（由适用提供）：败血症是一种高度致命的综合症，每年在联合国各州和全球有1800万人影响超过120万人。开发特定有效的药物需要更好地了解潜在的免疫组机制。先天免疫系统对于入侵病原体的敏感性和宿主免疫反应的激活至关重要。一套多样的种系编码的先天免疫受体调查了几乎所有细胞室，以使病原体及其产物存在。炎性症是含有NLR受体，适配器ASC和效应子caspase-1的细胞质中的多蛋白支架。炎症是细胞质免疫监测的组成部分。炎性症直接检测到各种“签名”微生物产物或与感染相关的间接感知体征。尽管革兰氏阴性细菌的脂多糖（LPS）被认为是通过Toll-like Receiver-4（TLR4）在细胞表面中仅检测到的，但最近已经描述了LPS在caspase-11中以TLR4独立的方式中的caspase-11中的caspase-11中的caspase caspase感测。细胞内LPS激活caspase-11导致caspase-1的蛋白水解活化，然后执行IL-1β和IL-18的激活。重要的是，活跃的caspase-11触发细胞死亡的炎症形式（凋亡）以及内源性警报蛋白或危险分子的释放，从而永久存在炎症反应。 LP的胞质敏感性和确保caspase-11激活是败血症的中心介体。尽管具有深远的临床意义，但该途径关于LPS胞质进入的分子基础的机械细节以及下游信号级联的调节仍然很少。这项研究旨在在三个特定目标中总体解决这些关键知识差距。 AIM 1和2将确定LPS如何进入细胞质并激活CASPASE-11，AIM 3将表征一种调节机制，该机制可在小鼠和人类的检查中保持炎症性caspase介导的免疫复杂。通过发现人类胞质LPS敏感性反应的分子细节，这项研究的发现可以提供新的免疫调节策略和靶标，以增强受保护的免疫力以及阻止检测器感染作为所需的感染性疾病。