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

• 批准号: 8488392
• 负责人: JEFFREY Scott SCHOREY
• 金额: $ 34.9万
• 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: 2004-03-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488392
• 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

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.

描述（由申请人提供）：分枝杆菌是艾滋病患者的主要机会病原体，也是肺部疾病患者肺部感染的主要原因。但是，缺乏我们对鸟藻发病机理的理解，部分原因是关于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（GPLS（GPLS）是许多在许多无结核病分枝杆菌中表达的主要表面成分，可以在将宿主反应引导到鸟杆菌感染中。我们发现，GPL可以参与模式识别受体Toll样受体2（TLR2），从而导致巨噬细胞激活。有趣的是，我们发现GPLS与TLR2相互作用的能力有所不同，而GPL乙酰化和甲基化模式的略有变化决定了这种糖脂能是否可以通过TLR2发出信号。 GPLS还可以吸引甘露糖受体，并且这种相互作用是对含有GPL涂层珠的吞噬体观察到的溶酶体标记的延迟指控所必需的。基于这些观察结果，我们假设M. avium可以在感染过程中修改其GPL结构，这是重要的毒力机制。此外，我们预测，大鸟肉对某些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GPL结构成分与MR结合所必需的以及其延迟吞噬体成熟的能力以及GPLS介导该延迟的机制。 2）表征巨噬细胞和小鼠感染后鸟杆菌菌株的GPL组成，并定义GPL组成与菌株毒力的相关性。 3）为参与GPL生物合成的基因生成大肠杆菌基因敲除突变体，并评估GPL介导的活性的突变体，包括通过TLR2和MR，生物膜形成和滑动运动以及小鼠感染模型中的毒力的信号传导。完成这些研究后，我们将更好地了解鸟雄发病机理以及GPLS在此过程中所起的作用以及获得的信息可能会导致开发新的诊断工具来评估鸟藻毒力。