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: 7034608
• 负责人: JEFFREY Scott SCHOREY
• 金额: $ 29.3万
• 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/7034608
• 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）：分枝杆菌是艾滋病患者的主要机会病原体，也是艾滋病毒感染个体发病率和死亡率增加的重要原因。鸟杆菌是一种巨噬细胞病原体，需要固定和侵袭其宿主细胞以促进疾病。然而，巨噬细胞在控制鸟杆菌感染中也起着至关重要的作用。因此，了解鸟杆菌发病机理的一个关键方面是定义对分枝杆菌的巨噬细胞反应，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。 我们已经启动了研究，以定义在鸟杆菌感染过程中激活的巨噬细胞信号通路，以及这种巨噬细胞的抗原性菌株在变化的致病性和致病性和非致病性分枝杆菌之间的差异。这些信号通路的激活对于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需的。我们的研究表明，感染致病性雄鸟的巨噬细胞显示有丝分裂原活化蛋白激酶（MAPK），环状AMP和其他信号分子相对于感染非致病分枝杆菌的细胞的有限激活。这种调整信号反应的结果是，鸟杆菌感染的巨噬细胞对TNF-Alpha，IL-1β和一氧化氮合酶的产生有限。因此，我们假设M. avium已经发展了机制以最大程度地减少MAPK和其他信号分子的激活，并且这种能力是其致病性的重要方面。糖肽脂质（GPL）是大鸟甲菌壁的一个良好特征成分，我们最近的数据表明，与含有GPLS的2151个形型感染的细胞相比，缺乏GPLS的M. avium 2151形态型感染了M. avium 2151形型。因此，我们建议：1）定义鸟杆菌在感染巨噬细胞中限制MAPK激活的机制2）确定GPLS在鸟杆菌发病机理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。