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：
7369901
负责人：
JEFFREY Scott SCHOREY
金额：
$ 30.78万
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 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7369901
关键词：
Acquired Immunodeficiency Syndrome Affect Anabolism Attenuated Bone Marrow Cell Wall Cells Data Effectiveness Family Genes Genus Mycobacterium Goals HIV Immune Immune response Individual Infection Infection Control Inflammatory Interleukin-12 Intervention Knowledge Lead Life Link MAPK14 gene Macrophage Activation Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Morbidity - disease rate Mus Mycobacterium Infections Mycobacterium avium Nitrogen Oxygen Pathogenesis Pathogenicity Pathway interactions Patients Phosphotransferases Play Process Production Relative (related person)Role Signal Pathway Signal Transduction Structure System TNF gene Time Transferase Tumor Necrosis Factor-alpha United States Virulence cytokine human TNF protein inhibitor/antagonist insight macrophage mitogen-activated protein kinase p38 mortality mutant mycobacterial novel pathogen research study response stress-activated protein kinase 1

项目摘要

DESCRIPTION (PROVIDED BY APPLICANT): Mycobacterial infections result in the activation of macrophage signaling pathways that are essential for stimulating a host immune response. However our understanding is limited as to which signaling pathways are transduced in macrophages upon mycobacterial invasion and whether pathogenic mycobacteria modulate these signals. In our experiments to define the macrophage signaling pathways initiated during a mycobacterial infection we determined that the mitogen activated protein kinases (MAPK) p38 and ERK 1/2 were activated in murine macrophages upon mycobacterial infection. However, the MAPK activity was limited in macrophages infected with pathogenic M. avium strains relative to cells infected with non-pathogenic mycobacteria. A limited production of TNF-alpha was also observed in these M. avium infected cells. Inhibitor studies indicated that the MAPKs were required for the mycobacteria-mediated induction of TNF-alpha. Moreover, macrophages infected with a glycopeptidolipid (GPL) deficient M. avium 2151 also showed increased MAPK activation and TNF-alpha production compared to cells infected with a isogenic 2151 strain containing GPLs. Therefore, we hypothesize that the MAPKs are key components in the macrophage signaling pathways initiated during a mycobacterial infection and that M. avium has evolved mechanisms to limit their activity in part through production of GPLs. Additional analysis showed that modifying the GPL structure through deletion of the methyl transferase D gene resulted in a M. avium 104 strain with attenuated virulence. Thus, we propose the following specific aims: 1) produce a panel of M. avium 724 and 104 mutants that lack specific genes involved in GPL biosynthesis 2) Biochemically characterize the M. avium mutants for GPL structure and cell wall composition 3) Characterize GPLs for their affect on macrophage activation and mycobacterial virulence. Our long-term goal is to better understand the macrophage signaling pathways initiated during a mycobacterial invasion. We believe a more careful analysis of these macrophage responses and how mycobacteria may modify them will lead to novel insights into mycobacterial pathogenesis.

描述（由申请人提供）：分枝杆菌感染导致激活巨噬细胞信号通路，这对于刺激宿主免疫反应至关重要。但是，我们的理解是有限的，即在分枝杆菌侵袭时在巨噬细胞中转导哪种信号通路以及致病性分枝杆菌是否调节这些信号。在我们的实验中，定义在分枝杆菌感染期间启动的巨噬细胞信号通路，我们确定有丝分裂原活化蛋白激酶（MAPK）p38和ERK 1/2在分枝杆菌感染后在鼠巨噬细胞中激活了菌丝。然而，相对于感染非致病性分枝杆菌的细胞，在感染了致病性鸟杆菌菌株的巨噬细胞中，MAPK活性受到限制。在这些鸟甲菌感染的细胞中也观察到了有限的TNF-α产生。抑制剂研究表明，MAPK是分枝杆菌介导的TNF-α诱导所必需的。此外，与感染了含有GPLS的同源性2151菌株的细胞相比，感染了糖肽（GPL）缺陷型硫胆脂（GPL）缺陷型M.鸟杆2151的巨噬细胞也显示出增加。因此，我们假设MAPK是分枝杆菌感染期间巨噬细胞信号通路中的关键组成部分，并且M. Avium具有进化的机制来部分通过GPLS的产生来限制其活性。附加分析表明，通过缺失甲基转移酶D基因来修饰GPL结构，导致avium 104菌株具有衰减的毒力。因此，我们提出以下特定目的：1）生产一组雄性雄性雄性雄性雄性大麻菌和104个突变体，这些突变体缺乏GPL生物合成的特定基因2）生物化学在生物化学上表征了GPL结构和细胞壁成分的雄性雄性雄性大麻菌突变体3）表征GPLS对巨噬细胞活化和支原体型的影响。我们的长期目标是更好地了解分枝杆菌入侵期间启动的巨噬细胞信号通路。我们认为，对这些巨噬细胞反应以及分枝杆菌如何改变它们的更仔细分析将导致对分枝杆菌发病机理的新见解。