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:
    6772770
  • 负责人:
  • 金额:
    $ 30.65万
  • 依托单位:
  • 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 2009-02-28
  • 项目状态:
    已结题

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(申请人提供):分枝杆菌感染导致巨噬细胞信号通路激活,这对刺激宿主免疫应答至关重要。然而,我们的理解是有限的,哪些信号转导途径在巨噬细胞后,分枝杆菌入侵和致病性分枝杆菌是否调节这些信号。 在我们的实验中,以确定巨噬细胞的信号转导途径,在分枝杆菌感染期间,我们确定有丝分裂原活化蛋白激酶(MAPK)p38和ERK 1/2被激活的小鼠巨噬细胞在分枝杆菌感染。而在感染M.相对于感染非致病性分枝杆菌的细胞,在这些M.病毒感染细胞。抑制剂研究表明,MAPKs是分枝杆菌介导的TNF-α诱导所必需的。此外,巨噬细胞感染糖肽脂(GPL)缺陷型M。与用含有GPL的同基因2151菌株感染的细胞相比,禽流感病毒2151也显示出增加的MAPK活化和TNF-α产生。因此,我们推测MAPKs是分枝杆菌感染时启动的巨噬细胞信号通路的关键成分,而M。鸟类已经进化出部分通过产生GPL来限制其活性的机制。进一步的分析表明,通过删除甲基转移酶D基因修饰GPL结构导致M。avium 104株弱毒。因此,我们提出了以下具体目标:1)产生一个面板的M。724和104个缺失GPL生物合成相关基因的突变体。3)表征GPL对巨噬细胞活化和分枝杆菌毒力的影响。我们的长期目标是更好地了解巨噬细胞的信号通路在分枝杆菌入侵启动。我们相信,对这些巨噬细胞反应以及分枝杆菌如何修饰它们进行更仔细的分析将导致对分枝杆菌发病机制的新见解。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)

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JEFFREY Scott SCHOREY其他文献

JEFFREY Scott SCHOREY的其他文献

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{{ truncateString('JEFFREY Scott SCHOREY', 18)}}的其他基金

Evaluating Mycobacterium avium glycopeptidolipids as key factors in the transition from biofilm to macrophages
评估鸟分枝杆菌糖肽脂作为从生物膜向巨噬细胞转变的关键因素
  • 批准号:
    10429772
  • 财政年份:
    2022
  • 资助金额:
    $ 30.65万
  • 项目类别:
Evaluating Mycobacterium avium glycopeptidolipids as key factors in the transition from biofilm to macrophages
评估鸟分枝杆菌糖肽脂作为从生物膜向巨噬细胞转变的关键因素
  • 批准号:
    10582714
  • 财政年份:
    2022
  • 资助金额:
    $ 30.65万
  • 项目类别:
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:
    8287661
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
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:
    6868878
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
Macrophage signaling upon M avium infection
鸟分枝杆菌感染时的巨噬细胞信号传导
  • 批准号:
    7034608
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
Macrophage signaling upon M avium infection
鸟分枝杆菌感染时的巨噬细胞信号传导
  • 批准号:
    7369902
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
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:
    7369901
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
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:
    7194264
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
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:
    8689879
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
Macrophage signaling upon M avium infection
鸟分枝杆菌感染时的巨噬细胞信号传导
  • 批准号:
    6745818
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
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