Molecular mechanisms of pathogen recognition by the Nod-like receptor NLRC4

Nod样受体NLRC4识别病原体的分子机制

• 批准号: 8195613
• 负责人: Fayyaz S. Sutterwala
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195613
• 关键词: Acute; Antibiotic-resistant organism; Antibiotics; Bacteremia; Bacteria; Bacterial Typing; Biology; Burn injury; C Type Lectin Receptors; Caspase-1; Cell Death; Cell membrane; Cells; Collaborations; Complex; Cysteine Protease; Cytosol; Environment; Event; Family member; Flagellin; Gram-Negative Bacteria; Immune; Immune response; Immune system; Immunologic Receptors; Infection; Inflammation; Inflammatory Response; Interleukin-12; Interleukin-18; Invaded; Lead; Legionella; Legionella pneumophila; Ligands; Light; Location; Mediating; Medical Device; Membrane; Mission; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Multiprotein Complexes; Mus; Nosocomial Infections; Opportunistic Infections; Organism; Pathogenesis; Pathway interactions; Patient Care; Pattern; Pattern recognition receptor; Pneumonia; Population; Predisposition; Prevalence; Principal Investigator; Process; Production; Pseudomonas; Pseudomonas aeruginosa; RNA Helicase; Reactive Oxygen Species; Relative (related person); Role; Salmonella; Salmonella typhimurium; Shigella; Shigella flexneri; Signal Pathway; Signal Transduction; Specificity; Sterility; Stimulus; Stress; System; TLR5 gene; Toll-like receptors; Transfection; Universities; Ventilator; caspase-3; combat; cystic fibrosis patients; cytokine; experience; in vivo; intraperitoneal; macrophage; monomer; mortality; mutant; neutrophil; new therapeutic target; novel; pathogen; patient population; programs; public health relevance; receptor; resistant strain; response; secretion process; sensor; superinfection

Project Summary Pseudomonas aeruginosa causes a variety of acute infections, such as ventilator-associated pneumonias, burn superinfections, neutropenic bacteremia, and medical device-related infections. In addition, P. aeruginosa chronically infects cystic fibrosis patients and causes significant morbidity and mortality in this population. With the increasing prevalence of antibiotic resistant organisms, developing agents that will modulate host immune responses will be key adjunctive treatments to conventional antibiotics in combating pathogens such as P. aeruginosa. In order to do this a detailed understanding of the innate immune pathways involved in recognition of pathogens such as P. aeruginosa are required. In this proposal we will examine the role of the NOD-like receptor (NLR) family member NLRC4 in recognition and response to infection with P. aeruginosa. In macrophages NLRC4 is activated in a multiprotein complex called the inflammasome upon infection with a wide variety of Gram-negative bacteria. The activation of the NLRC4 inflammasome ultimately results in the activation of the cysteine protease caspase-1 and its processing and secretion of proinflammatory cytokines. P. aeruginosa activates caspase-1 in an NLRC4-dependent manner leading to macrophage cell death and the release of interleukin (IL)-1¿ and IL-18. NLRC4-deficient mice also demonstrate increased susceptibility to infection with P. aeruginosa in vivo. In addition to Pseudomonas, other Gram-negative bacteria such as Salmonella, Legionella and Shigella have also been found to activate the NLRC4 inflammasome. One factor that is common to all these pathogens, and required for NLRC4 inflammasome activation, is a functional bacterial type III (T3SS) or type IV (T4SS) secretion system. However, it still remains unclear if NLRC4 serves as a cytosolic pattern recognition receptor for bacterial compounds that gain entry into the cytosol of the host cell through T3SS or T4SS, or if it indirectly senses the consequences of plasma membrane damage caused by the bacterial secretion systems. This proposal outlines three novel aims that will examine the molecular mechanism involved in activation of NLRC4: i) Defining the molecular components and cellular location for assembly of the NLRC4 inflammasome. ii) Elucidating the role of Toll-like receptors and reactive oxygen species in the upstream signaling pathways leading to NLRC4 inflammasome activation. iii) Determining if NLRC4 recognizes host plasma membrane components following their disruption by bacterial T3SS.

项目摘要 铜绿假单胞菌可引起多种急性感染，如呼吸机相关性感染 肺炎、烧伤重叠感染、中性粒细胞减少菌血症和医疗器械相关感染。此外, 铜绿假单胞菌慢性感染囊性纤维化患者，并导致显著的发病率和死亡率。 人口。随着抗生素耐药性生物的日益普遍，开发出的试剂将 调节宿主免疫反应将是对抗常规抗生素的关键辅助治疗 病原体，如铜绿假单胞菌。为了做到这一点，我们需要详细了解先天免疫途径。 需要参与识别铜绿假单胞菌等病原体。在本提案中，我们将研究 Nod样受体(NLR)家族成员NLRC4在识别和应答肺炎支原体感染中的作用 铜绿假单胞菌。在巨噬细胞中，NLRC4在一种称为炎症小体的多蛋白复合体中被激活 感染多种革兰氏阴性细菌。NLRC4炎症体的最终激活 结果半胱氨酸蛋白酶caspase-1的激活及其加工和分泌 促炎细胞因子。铜绿假单胞菌以NLRC4依赖的方式激活caspase-1，导致 巨噬细胞死亡和IL-1、IL-18的释放。NLRC4缺陷小鼠也 在体内证明对铜绿假单胞菌感染的易感性增加。除假单胞菌外，其他 革兰氏阴性细菌，如沙门氏菌、军团菌和志贺氏菌也被发现激活 NLRC4炎症体。所有这些病原体共有的一个因素，也是NLRC4所必需的 炎性小体激活，是一种功能性细菌III型(T3SS)或IV型(T4SS)分泌系统。然而， 目前仍不清楚NLRC4是否作为细菌化合物的细胞质模式识别受体 通过T3SS或T4SS进入宿主细胞的胞浆，或者如果它间接感觉到 细菌分泌系统造成质膜损伤。这项提议概述了三个新颖的目标 这将检查NLRC4激活所涉及的分子机制：i)定义分子 用于组装NLRC4炎症体的组件和细胞位置。二)阐明Toll-like的作用 NLRC4炎症体上游信号通路中的受体和活性氧物种 激活。三)确定NLRC4在被破坏后是否识别宿主质膜成分 细菌T3SS。