THE ROLE OF THE NON-CANONICAL INFLAMMASOME IN INNATE IMMUNITY

非典型炎症小体在先天免疫中的作用

• 批准号: 10310743
• 负责人: Amal O Amer
• 金额: $ 75.53万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-11 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10310743
• 关键词: 3-Dimensional; Actins; Autophagocytosis; Autophagosome; Bacteria; CASP1 gene; Cancer Patient; Caspase; Cell Death; Cell membrane; Cells; Cleaved cell; Complex; Confocal Microscopy; Cytoskeleton; Data; Down-Regulation; Elderly; Eukaryotic Cell; Event; F-Actin; Gelsolin; Gram-Negative Bacteria; Growth; Human; Immune; Immunocompromised Host; In Vitro; Individual; Infection; Inflammasome; Inflammatory; Interleukin-1 beta; Legionella; Legionella pneumophila; Legionnaires' Disease; Lysosomes; Mediating; Molecular; Morbidity - disease rate; Mus; N-terminal; Natural Immunity; Organelles; Peptide Hydrolases; Phagocytes; Phenotype; Physiological; Process; Proteins; Proteomics; Publishing; Recombinants; Reporting; Resolution; Role; Site; Spectrometry, Mass, Secondary Ion; Techniques; Testing; Three-dimensional analysis; Time; Vacuole; antimicrobial; cofilin; depolymerization; in vivo; macrophage; mortality; neutrophil; novel; older patient; pathogen; pathogenic bacteria; permissiveness; polymerization; response; transcriptome sequencing

ABSTRACT Legionella pneumophila is an infectious bacterium that causes Legionnaire’s disease and remains a major cause of morbidity and mortality in the immunocompromised individuals such as the elderly and cancer patients. Macrophages are the main immune cells that can clear Legionella after activation of the canonical Nlrc4/Naip5 inflammasome. Caspase-11 is a component of the non-canonical inflammasome and mice lacking caspase-11 allow significant Legionella replication in their macrophages. Down-regulation of the homologous caspase in human macrophages increases their permissiveness to Legionella. Our preliminary data show that caspase-11 is necessary for fusion of the Legionella-containing vacuole with the lysosomes via a mechanism that requires the polymerization and depolymerization of actin. Using state-of-the-art techniques including 3D confocal microscopy and high resolution SIM-S microscopy, RNA seq and proteomics analyses, we identified new molecules that are cleaved by caspase-11 and regulate restriction of Legionella in macrophages. This proposal will investigate the molecular mechanisms leading to caspase-11-mediated clearing of Legionella infection.

摘要 嗜肺军团菌是一种引起军团病的传染性细菌，至今仍是主要病因 免疫功能低下的个体如老年人和癌症患者的发病率和死亡率。 巨噬细胞是典型的Nlrc 4/Naip 5激活后清除军团菌的主要免疫细胞 炎性小体Caspase-11是非典型炎性小体的组成部分，缺乏Caspase-11的小鼠 允许军团菌在巨噬细胞中大量复制。同源半胱天冬酶在细胞凋亡中的下调 人巨噬细胞增加了它们对军团菌的容许性。我们的初步数据显示caspase-11 是通过一种机制将含有军团菌的空泡与溶酶体融合所必需的， 肌动蛋白的聚合和解聚。使用最先进的技术，包括3D共聚焦 显微镜和高分辨率SIM-S显微镜，RNA测序和蛋白质组学分析，我们发现了新的 被胱天蛋白酶-11切割并调节巨噬细胞中军团菌限制的分子。这项建议 将研究导致半胱天冬酶-11介导的军团菌感染清除的分子机制。