M. avium GPLs in Macrophage Activation and Virulence

M. avium GPL 在巨噬细胞激活和毒力中的作用

基本信息

批准号：
8287661
负责人：
JEFFREY Scott SCHOREY
金额：
$ 37.13万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8287661
关键词：
Acetylation Acquired Immunodeficiency Syndrome Affect Amides Amino Alcohols Anabolism Bacteria Binding Breathing Development Diagnosis Disease Fatty Acids Food Genes Genus Mycobacterium Glycolipids Goals HIV Human Immune Immune response Individual Infection Ingestion Invaded Knock-out Lead Length Link Lipids Lung Lung diseases Macrophage Activation Mediating Methods Methylation Microbial Biofilms Modeling Modification Morbidity - disease rate Mus Mycobacterium Infections Mycobacterium avium Mycobacterium avium Complex Pathogenesis Pathogenicity Patients Pattern Pattern recognition receptor Phagosomes Play Recurrence Research Rhamnose Role Serotyping Signal Transduction Slide Soil Source Structure Surface Testing Toll-Like Receptor 2 Tuberculosis United States Variant Virulence Virulence Factors Water Supply aerosolized base cell motility information processing macrophage mannose receptor mortality mutant non-tuberculosis mycobacteria novel diagnostics pathogen public health relevance sugar tool transmission process

项目摘要

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.

描述（由申请人提供）：鸟分枝杆菌是艾滋病患者的主要机会病原体，也是患有潜在肺部疾病的个体肺部感染的主要原因。然而，我们对鸟分枝杆菌发病机制的了解缺乏，部分原因是有关调节宿主反应的鸟分枝杆菌成分的信息有限。然而，先前的研究表明，糖肽脂（GPL）是许多非结核分枝杆菌表达的主要表面成分，可能在指导宿主对鸟分枝杆菌感染的反应中发挥作用。我们发现 GPL 可以与模式识别受体 Toll 样受体 2 (TLR2) 结合，从而导致巨噬细胞激活。有趣的是，我们发现 GPL 与 TLR2 相互作用的能力各不相同，并且 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，并且这种相互作用对于在含有 GPL 包被珠的吞噬体中观察到的溶酶体标记物的延迟指控是必需的。基于这些观察，我们假设鸟分枝杆菌可以在感染过程中改变其 GPL 结构，这是一种重要的毒力机制。此外，我们预测鸟分枝杆菌某些 GPL 变体的表达增加将与菌株的致病性相关。为了测试这些预测，我们将： 1) 定义其与 MR 结合所需的 GPL 结构组件、延迟吞噬体成熟的能力以及 GPL 介导这种延迟的机制。 2) 描述巨噬细胞和小鼠感染后鸟分枝杆菌菌株的 GPL 组成，并定义 GPL 组成如何与菌株毒力相关。 3) 生成参与 GPL 生物合成的基因的鸟分枝杆菌敲除突变体，并评估突变体的 GPL 介导活性，包括通过 TLR2 和 MR 的信号传导、生物膜形成和滑动运动以及小鼠感染模型中的毒力。完成这些研究后，我们将更好地了解鸟分枝杆菌的发病机制以及 GPL 在此过程中发挥的作用，所获得的信息可能有助于开发新的诊断工具来评估鸟分枝杆菌毒力。公共卫生相关性：鸟分枝杆菌是艾滋病患者的主要机会病原体，也是艾滋病毒感染者发病和死亡的重要原因。它也是患有潜在肺部疾病的个体肺部感染的常见原因。该提案的目标是更好地了解鸟分枝杆菌的发病机制，以便开发限制鸟分枝杆菌感染和治疗感染者的新方法。