Role of caspases in Legionella pneumophila pulmonary infection

半胱天冬酶在嗜肺军团菌肺部感染中的作用

• 批准号: 8079013
• 负责人: Amal O Amer
• 金额: $ 37.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079013
• 关键词: A/J Mouse; Acquired Immunodeficiency Syndrome; Adaptor Signaling Protein; Adult; Affect; Alveolar Macrophages; Bacteria; Binding; Biological; Cancer Patient; Case Study; Caspase; Caspase-1; Cell Death; Cells; Cessation of life; Cleaved cell; Disease; Elderly; Event; Flagellin; Genes; Goals; Growth; Health; Human; Immune; Immunity; In Vitro; Incidence; Individual; Infection; Inflammation; Lead; Legionella; Legionella pneumophila; Legionellosis; Legionnaires' Disease; Lung; Lysosomes; Mass Spectrum Analysis; Mediating; Microbe; Molecular; Mus; Nucleotides; Organism; Pathway interactions; Patients; Phagocytes; Phagosomes; Pneumonia; Proteins; Proteomics; Resistance; Role; Testing; United States; Wild Type Mouse; base; caspase-7; combat; design; in vivo; macrophage; middle age; monocyte; mutant; novel; novel strategies; pathogen; response; trafficking

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.

描述（由申请人提供）：胱天蛋白酶在肺炎军团肺肺部感染中的作用。肺炎军团菌（L. pneumophila）是一种细菌，会引起军团疾病，这是一种以严重肺炎为特征的人类疾病，影响了老年人和免疫受损的个体。每年在美国报告200,000例案件，8,000-18,000名军团病患者的死亡率高达30％。作为肺部的第一道防线，巨噬细胞吞噬了细菌。然而，一些病原体（如肺炎乳杆菌）具有制服该吞噬细胞并建立感染的策略。肺炎乳杆菌能够在人巨噬细胞中繁殖，而小鼠细胞对肺炎乳杆菌具有抗性，除了缺乏IPAF，caspase-1或含​​有突变的Naip5基因的小鼠外。 IPAF是一种接头蛋白，可感知细胞内细菌鞭毛蛋白，从而导致caspase-1的激活。激活后，caspase-1切开特定的底物，导致细胞中的不同事件。然而，胱天蛋白酶在细胞死亡中的作用主要被考虑，并且缺乏对胱天蛋白酶其他功能的研究。新兴研究表明，除了诱导细胞死亡外，胱天蛋白酶在细胞中具有重要功能。我们假设胱天蛋白酶可以通过调节吞噬体溶酶体融合事件的调节，从而控制细胞内细菌的命运，这将导致细菌清除。使用缺乏不同胱天蛋白酶及其衍生巨噬细胞的小鼠，我们将研究胱天蛋白酶在决定细胞内细菌命运方面的新作用。我们将辨别NOD蛋白NAIP5在胱天蛋白酶激活中的作用。该项目将确定控制肺炎乳杆菌成熟的机理。这项研究最终将实现新分子的设计，这些新分子可以专门针对特定的胱天蛋白酶并操纵含有细胞内肺病原体的吞噬体的成熟。这将代表一种新颖的方法来治疗和管理肺部感染和炎症。公共卫生相关性：肺炎军团菌是一种细菌，可能引起严重的肺炎，尤其是在老年人和免疫力低的个体中导致死亡。我们建议研究这种肺病原体如何建立感染并引起疾病。我们的长期目的是使用这些信息来设计分子来对抗军团菌和其他肺微生物。