M. avium GPLs in Macrophage Activation and Virulence

描述（由申请人提供）：鸟分枝杆菌是艾滋病患者的主要机会致病菌，也是潜在肺部疾病患者肺部感染的主要原因。然而，我们对M.禽支原体的发病机制缺乏，部分原因是关于M.鸟类的成分参与调节宿主的反应。然而，先前的研究表明，糖肽脂（GPLs），这是许多非结核分枝杆菌表达的主要表面成分，可能在指导宿主对M。禽流感我们已经发现，GPL可以接合模式识别受体Toll样受体2（TLR2），导致巨噬细胞活化。有趣的是，我们发现GPL与TLR2相互作用的能力不同，GPL乙酰化和甲基化模式的轻微变化决定了这种糖脂是否可以通过TLR2发出信号。GPL还可以与甘露糖受体结合，并且这种相互作用是在含有GPL包被珠粒的吞噬体中观察到的溶酶体标记物的延迟指控所必需的。基于这些观察，我们假设M。禽流感病毒在感染过程中可以改变其GPL结构，这是一个重要的毒力机制。此外，我们预测M.禽流感病毒的致病性与菌株的致病性相关。为了测试这些预测，我们将：1）定义GPL与MR结合所必需的结构组件，以及其延迟吞噬体成熟的能力和GPL介导这种延迟的机制。2)描述M的GPL组成。禽流感病毒株后，巨噬细胞和小鼠感染，并确定如何GPL组成与菌株的毒力。3)生成M。本发明的目的是检测参与GPL生物合成的基因的禽流感基因敲除突变体，并评估突变体的GPL介导的活性，包括通过TLR2和MR的信号传导、生物膜形成和滑动运动性，以及在小鼠感染模型中的毒力。通过这些研究，我们将对M.禽支原体的发病机制和GPL在此过程中的作用以及所获得的信息可能会导致新的诊断工具的发展，以评估M。禽毒力 公共卫生相关性：鸟分枝杆菌（Mycobacterium avium）是艾滋病（AIDS）患者的主要机会致病菌，也是HIV感染者发病和死亡的重要原因。它也是潜在肺部疾病患者肺部感染的常见原因。这个建议的目的是为了更好地理解M。研究禽支原体的致病机理，以开发新的限制禽支原体的方法。禽流感感染和治疗感染者。

DESCRIPTION (provided by applicant): Mycobacterium avium is a major opportunistic pathogen in AIDS patients as well as a major cause of pulmonary infection in individuals with underlying lung disease. However, our understanding of M. avium pathogenesis is lacking due in part to limited information on M. avium components involved in modulating the host response. Nevertheless, previous studies suggest that glycopeptidolipids (GPLs), which are major surface components expressed on many non-tuberculosis mycobacteria, may function in directing the host response to an M. avium infection. We have found that GPLs can engage the pattern recognition receptor Toll-like receptor 2 (TLR2) leading to macrophage activation. Interestingly, we found that GPLs varied in their ability to interact with TLR2 and that slight changes in the GPL acetylation and methylation patterns determine whether this glycolipid can signal through TLR2. GPLs can also engage the mannose receptor and that this interaction is required for the delayed accusation of lysosomal markers observed for phagosomes containing GPL-coated beads. Based on these observations we hypothesize that M. avium can modify its GPL structure during the course of an infection and that this is an important virulence mechanism. Further, we predict that increased expression of certain GPL variants by M. avium will correlate with a strain's pathogenicity. To test these predictions we will: 1) Define the GPL structural components necessary for its binding to the MR and for its ability to delay phagosome maturation and the mechanism by which GPLs mediate this delay. 2) Characterize the GPL composition of M. avium strains following macrophage and mouse infections and define how the GPL composition correlates with strain virulence. 3) Generate M. avium knockout mutants for genes involved in GPL biosynthesis and evaluate the mutants for GPL-mediated activities including signaling through TLR2 and MR, biofilm formation and sliding motility and for virulence in a mouse infection model. Upon completion of these studies we will have a better understanding of M. avium pathogenesis and the role that GPLs play in this process and the information garnered may lead to the development of new diagnostic tools to evaluate M. avium virulence. PUBLIC HEALTH RELEVANCE: Mycobacterium avium is a major opportunistic pathogen in AIDS patients and a significant cause of morbidity and mortality in HIV infected individuals. It is also a common cause of pulmonary infections in individuals with underlying lung disease. The goal of this proposal is to better understand M. avium pathogenesis so as to develop new methods to limit M. avium infections and to treat those infected.