Macrophage signaling upon M avium infection

描述（由申请方提供）：鸟分枝杆菌是艾滋病患者的主要机会致病菌，也是HIV感染者发病率和死亡率增加的重要原因。M.禽流感是一种巨噬细胞内的病原体，其需要附着和侵入其宿主细胞以引发疾病。然而，巨噬细胞在控制M.禽流感因此，理解M.禽结核病的发病机制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。 我们已经开始了研究，以确定M。禽流感病毒感染和M.不同致病性的禽分枝杆菌菌株以及致病性和非致病性分枝杆菌之间。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、趋化因子和其它效应分子的产生是必需的。我们的研究表明，感染致病性M。相对于感染非致病性分枝杆菌的细胞，禽分枝杆菌显示出有限的促分裂原活化蛋白激酶（MAPK）、环AMP和其它信号分子的活化。这种缓和的信号应答的结果是M.禽流感病毒感染的巨噬细胞。因此，我们假设M.禽流感病毒已经进化出使MAPK和其他信号分子的激活最小化的机制，并且这种能力是其致病性的一个重要方面。糖肽脂（GPL）是M.我们最近的数据表明，感染M.与用含有GPL的2151形态型感染的细胞相比，缺乏GPL的鸟2151形态型具有延长的MAPK活化。因此，我们建议：1）定义的机制，通过M。2）确定GPL在M.禽流感发病机制和巨噬细胞活化。我们将使用遗传学、免疫学和细胞生物学方法的组合来解决这些重要问题。

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.