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: 6745818
• 负责人: JEFFREY Scott SCHOREY
• 金额: $ 28.75万
• 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/6745818
• 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性病原体，也是HIV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，它需要附着和侵入宿主细胞来引发疾病。然而，巨噬细胞在控制鸟分枝杆菌感染中也起着至关重要的作用。因此，了解鸟分枝杆菌发病机制的一个关键方面是确定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。