Macrophage signaling upon M avium infection

描述(申请人提供)：鸟分枝杆菌是艾滋病患者的一种主要的机会性病原体，也是艾滋病毒感染者发病率和死亡率增加的重要原因。禽类支原体是一种巨噬细胞内的病原体，它需要宿主细胞的附着和入侵才能引发疾病。然而，巨噬细胞在控制禽类支原体感染方面也起着至关重要的作用。因此，理解禽类分枝杆菌致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。 我们已经开始了研究，以确定在禽类分支杆菌感染期间激活的巨噬细胞信号通路，以及不同致病性的禽类分支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。这些信号通路的激活是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所必需的。我们的研究表明，与感染非致病性分枝杆菌的细胞相比，感染致病性禽类分支杆菌的巨噬细胞显示出有限的丝裂原活化蛋白激酶(MAPK)、环磷酸腺苷(CAMP)和其他信号分子的激活。这种缓和的信号反应的结果是限制了感染禽类支原体的巨噬细胞产生肿瘤坏死因子-α、白介素1-β和一氧化氮合酶。因此，我们推测，鸟型支原体已经进化出将MAPK和其他信号分子的激活降到最低的机制，这种能力是其致病性的一个重要方面。糖肽多脂(GPL)是禽类支原体细胞壁的一种典型成分，我们最近的数据表明，与感染含有GPL的2151型支原体的巨噬细胞相比，感染缺乏GPL的2151型支原体的巨噬细胞具有更长的MAPK激活时间。因此，我们建议：1)明确禽类支原体限制感染巨噬细胞MAPK激活的机制；2)确定GPLs在禽类支原体致病和巨噬细胞活化中的重要性。我们将结合使用遗传学、免疫学和细胞生物学的方法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.