Role of caspases in Legionella pneumophila pulmonary infection

描述（由申请人提供）：半胱天冬酶在嗜肺军团菌肺部感染中的作用。嗜肺军团菌（L. pneumophila）是一种引起军团病的细菌，军团病是一种以严重肺炎为特征的人类疾病，影响老年人和免疫功能低下者。美国每年报告20万例军团菌病病例，8000 - 18000名军团菌病患者住院治疗，死亡率高达30%。作为肺部的第一道防线，巨噬细胞吞噬并降解细菌。然而，一些病原体如嗜肺乳杆菌有策略来抑制这种吞噬细胞并建立感染。嗜肺乳杆菌能够在人巨噬细胞内繁殖，而小鼠细胞对嗜肺乳杆菌有抗性，但缺乏Ipaf、caspase-1或携带突变基因Naip5的小鼠除外。Ipaf是一种NOD蛋白，可感知细胞内细菌鞭毛蛋白，导致caspase-1的激活。一旦被激活，caspase-1就会切割特定的底物，导致细胞内发生不同的事件。然而，caspases主要被认为在细胞死亡中起作用，对caspases的其他功能的研究缺乏。新的研究表明，半胱天冬酶除了诱导细胞死亡外，在细胞中还具有重要的功能。我们假设半胱天冬酶可以通过调节吞噬体溶酶体融合事件来控制细胞内细菌的命运，如嗜肺杆菌。利用缺乏不同半胱天冬酶的小鼠及其衍生的巨噬细胞，我们将研究半胱天冬酶在决定细胞内细菌命运中的新作用。我们将发现NOD蛋白Naip5在caspase激活中的作用。本课题旨在研究嗜肺乳杆菌吞噬体成熟的调控机制。这项研究最终将能够设计出能够特异性靶向特定半胱天冬酶的新分子，并操纵含有细胞内肺病原体的吞噬体的成熟。这将代表一种治疗和管理肺部感染和炎症的新方法。公共卫生相关性：嗜肺军团菌是一种可引起严重肺炎的细菌，特别是在老年人和免疫力低下的个体中，可导致死亡。我们建议研究这种肺部病原体如何建立感染并引起疾病。我们的长期目标是利用这些信息来设计对抗军团菌和其他肺部微生物的分子。

DESCRIPTION (provided by applicant): Role of caspases in Legionella pneumophila pulmonary infection. Legionella pneumophila (L. pneumophila) is a bacteriumthat causes Legionnaires' disease, a human illness characterized by severe pneumonia that affects the elderly and the immune-compromised individuals. Annually, 200,000 cases are reported in the United States and 8,000-18,000 people with legionellosis are hospitalized with fatality rates up to 30%. As a first line of defense in the lungs, macrophages engulf and degrade bacteria. However, some pathogens like L. pneumophila have strategies to subdue this phagocytic cell and establish infection. L. pneumophila is capable of multiplying within human macrophages whereas mice cells are resistant to L. pneumophila with the exception of mice lacking Ipaf, caspase-1 or harboring a mutant Naip5 gene. Ipaf is a NOD protein that senses intracellular bacterial flagellin leading to activation of caspase-1. Once activated, caspase-1 cleaves specific substrates leading to different events in the cell. However, caspases have been mainly considered for their role in cell death and studies on other functions of caspases have been lacking. Emerging studies suggest that caspases have important functions in the cell in addition to inducing cell death. We hypothesize that caspases can control the fate of intracellular bacteria like L pneumophila through the modulation of phagosome lysosome fusion events that will lead to bacterial clearance. Using mice lacking different caspases and their derived macrophages, we will investigate the novel role of caspases in dictating the fate of intracellular bacteria. We will discern the role of the NOD protein Naip5 in caspase activation. This project will determine the mechanism of control of L. pneumophila phagosome maturation. This study will ultimately enable the design of new molecules that can specifically target particular caspases and manipulate the maturation of phagosomes containing intracellular lung pathogens. This will represent a novel approach to the treatment and management of infection and inflammation in the lung. PUBLIC HEALTH RELEVANCE: Legionella pneumophila is a bacterium that can cause severe pneumonia especially in the elderly and in individuals with low immunity leading to death. We propose to study how this lung pathogen can establish infection and cause disease. Our long term aim is to use this information to design molecules to combat Legionella and other lung microbes.