THE ROLE OF THE NON-CANONICAL INFLAMMASOME IN INNATE IMMUNITY

摘要 嗜肺军团菌是一种引起军团病的传染性细菌，至今仍是主要原因 关于老年人和癌症患者等免疫功能受损个体的发病率和死亡率。 巨噬细胞是典型的NLRC4/Naip5激活后清除军团菌的主要免疫细胞 炎症者。Caspase-11是非典型炎症体的一种成分，而缺乏caspase-11的小鼠 允许军团菌在他们的巨噬细胞中显著复制。同源半胱氨酸天冬氨酸酶的表达下调 人巨噬细胞对军团菌的易感性增加。我们的初步数据显示，caspase-11 是含有军团菌的液泡与溶酶体融合所必需的，这种机制需要 肌动蛋白的聚合和解聚。使用最先进的技术，包括3D共焦 显微镜和高分辨率SIM-S显微镜，RNA序列和蛋白质组分析，我们发现了新的 被caspase-11裂解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caspase-11介导的军团菌感染清除的分子机制。

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.