How can caspases control intracellular pulmonary pathogens

描述(由申请人提供)：嗜肺军团菌(军团菌)是一种名为军团病的严重肺炎的病原体。退伍军人症主要影响老年人和免疫功能低下的人。在美国，每年有8000-18000名军团菌病患者住院治疗，病死率从5%到30%不等。最近，美国的军团菌病发病率突然增加，特别是在中年人中。此外，最近的研究报告说，艾滋病和癌症患者中也出现了军团菌感染。因此，任何肺炎患者的鉴别诊断都应考虑军团菌感染。 军团菌在巨噬细胞内的复制对这种疾病至关重要，因为在体外细胞内生长有缺陷的突变株无法在体内引起肺炎。人的巨噬细胞对军团菌感染很敏感。而除A/J、caspase-1-/-和IPAF-/-小鼠外，大多数小鼠品系对军团菌具有抗药性。军团菌通过NOD受体IPAF激活caspase-1，导致吞噬小体-溶酶体融合和细菌杀灭。然而，其他caspase在军团菌感染中的作用仍不清楚。 我们的初步结果表明，在感染小鼠巨噬细胞后，一些caspase被激活，而不依赖于典型的凋亡途径。值得注意的是，缺乏这些半胱氨酸酶的巨噬细胞允许军团菌大量复制。因此，我们建议研究某些caspase的激活对肺部病原体命运的影响，并了解这些分子控制细胞内感染的机制。 这项工作将揭示caspase激活的新机制，并探索caspase在宿主防御细胞内细菌中的新生物学作用。此外，从这项研究中获得的信息将使设计能够针对特定半胱氨酸酶的分子来控制肺部感染。公共卫生相关性：嗜肺军团菌是一种可导致严重肺炎的细菌，尤其是在老年人中。目前尚不清楚军团菌如何在人类宿主细胞中持续存在并繁殖致病。这个项目将有助于了解细菌如何建立感染，以及宿主细胞如何对这种细胞内病原体做出反应。因此，我们的目标将导致更好地管理细胞内感染。

DESCRIPTION (provided by applicant): Legionella pneumophila (Legionella) is the causative agent of a severe pneumonia called Legionnaires' disease. Legionnaires' disease affects mainly the elderly and immune-compromised individuals. Each year, 8,000-18,000 people with legionellosis are hospitalized in the United States and fatality rates vary from 5% to 30%. Recently, an abrupt increase in the incidence of legionellosis in the United States has been noted, particularly among middle aged adults. Furthermore, recent studies reported that Legionella infection has emerged in AIDS and in cancer patients. Therefore, Legionella infection should be considered in the differential diagnosis of any patient with pneumonia. The replication of Legionella within macrophages is critical for the disease, as mutants defective for intracellular growth in vitro are unable to cause pneumonia in vivo. Human macrophages are susceptible to Legionella infection. Whereas most mouse strains are resistant to Legionella with the exception of the A/J, caspase-1-/- and Ipaf-/- mice. The activation of caspase-1 is provoked by Legionella through the NOD receptor Ipaf, leading to robust phagosome-lysosome fusion and bacterial killing. However, the role of other caspases in Legionella infection is still unknown. Our preliminary results show that upon infection of murine macrophages, some caspases were activated independent of the typical apoptosis pathway. Remarkably, macrophages lacking these caspases allowed substantial Legionella replication. Therefore, we propose to study the effect of activation of certain caspases on the fate of the lung pathogen and understand the mechanism by which these molecules control intracellular infection. This work will reveal a new mechanism for caspase activation and explore a novel biological role for caspases in host defense against an intracellular bacterium. Furthermore, information gained from this study will allow the design of molecules that can target specific caspases to control pulmonary infections. PUBLIC HEALTH RELEVANCE: Legionella pneumophila is a bacterium that can cause severe pneumonia especially in the elderly. It is not known how Legionella persists in the human host cell and multiplies to cause disease. This project will help understand how bacteria establish infection, and how the host cell responds to this intracellular pathogen. Therefore, our aims will lead to better management of intracellular infections.