Macrophage signaling upon M avium infection

鸟分枝杆菌感染时的巨噬细胞信号传导

• 批准号: 6855124
• 负责人: JEFFREY Scott SCHOREY
• 金额: $ 30万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855124
• 关键词: Mycobacterium avium; bacterial cytopathogenic effect; biological signal transduction; cyclic AMP; enzyme activity; glycopeptides; immunoprecipitation; laboratory mouse; leukocyte activation /transformation; macrophage; mitogen activated protein kinase; phosphorylation; polymerase chain reaction; virulence; western blottings

DESCRIPTION (provided by applicant): Mycobacterium avium is a major opportunistic pathogen in AIDS patients and a significant cause of increased morbidity and mortality in HIV infected individuals. M. avium is an intra-macrophage pathogen which requires attachment and invasion of its host cell to initiate disease. However, macrophages also play an essential role in controlling a M. avium infection. Therefore, a key aspect to the understanding of M. avium pathogenesis is to define the macrophage response to the mycobacteria and how the bacilli modulates this response to limit the macrophage's ability to control the infection. We have initiated studies to define the macrophage signaling pathways activated during a M. avium infection and how this differs between M. avium strains of varied pathogenicity and between pathogenic and non-pathogenic mycobacteria. The activation of these signaling pathways are necessary for the production of cytokines, chemokines and other effector molecules required to control a mycobacterial infection. Our studies have shown that macrophages infected with pathogenic M. avium show limited activation of the mitogen activated protein kinases (MAPK), cyclic AMP and other signaling molecules relative to cells infected with non-pathogenic mycobacteria. The consequence of this tempered signaling response is limited production of TNF-alpha, IL-1 beta and nitric oxide synthase by the M. avium infected macrophages. Therefore, we hypothesize that M. avium has evolved mechanisms to minimize the activation of the MAPK and other signaling molecules and that this ability is an important aspect of its pathogenicity. The glycopeptidolipids (GPL) are one well-characterized component of the M. avium cell wall and our recent data indicate that macrophages infected with a M. avium 2151 morphotype which lacks GPLs has prolonged MAPK activation compared to cells infected with a 2151 morphotype containing GPLs. Therefore we propose to: 1) Define the mechanism by which M. avium limits MAPK activation in infected macrophages 2) Determine the importance of GPLs in M. avium pathogenesis and in macrophage activation. We will use a combination of genetic, immunological and cell biological approaches to address these important questions.

描述（由申请人提供）：鸟分枝杆菌是艾滋病患者的主要机会病原体，也是艾滋病毒感染者发病率和死亡率增加的重要原因。鸟分枝杆菌是一种巨噬细胞内病原体，需要附着和侵入宿主细胞才能引发疾病。然而，巨噬细胞在控制鸟分枝杆菌感染中也发挥着重要作用。因此，了解鸟分枝杆菌发病机制的一个关键方面是定义巨噬细胞对分枝杆菌的反应以及杆菌如何调节这种反应以限制巨噬细胞控制感染的能力。 我们已经启动研究来定义鸟分枝杆菌感染期间激活的巨噬细胞信号通路，以及不同致病性的鸟分枝杆菌菌株之间以及致病性和非致病性分枝杆菌之间的差异。这些信号传导途径的激活对于产生控制分枝杆菌感染所需的细胞因子、趋化因子和其他效应分子是必要的。我们的研究表明，与感染非致病性分枝杆菌的细胞相比，感染致病性鸟分枝杆菌的巨噬细胞对丝裂原激活蛋白激酶（MAPK）、环磷酸腺苷和其他信号分子的激活有限。这种缓和的信号反应的结果是受鸟分枝杆菌感染的巨噬细胞产生的TNF-α、IL-1β和一氧化氮合酶受到限制。因此，我们假设鸟分枝杆菌已经进化出最小化 MAPK 和其他信号分子激活的机制，并且这种能力是其致病性的一个重要方面。糖肽脂 (GPL) 是鸟分枝杆菌细胞壁的一种众所周知的成分，我们最近的数据表明，与感染含有 GPL 的 2151 形态型的细胞相比，感染缺乏 GPL 的鸟分枝杆菌 2151 形态型的巨噬细胞具有更长的 MAPK 激活时间。因此，我们建议： 1) 定义鸟分枝杆菌限制受感染巨噬细胞中 MAPK 激活的机制 2) 确定 GPL 在鸟分枝杆菌发病机制和巨噬细胞激活中的重要性。我们将结合遗传、免疫学和细胞生物学方法来解决这些重要问题。