Intracellular Bacterial Recognition in the Drosophila Innate Immune Response

果蝇先天免疫反应中的细胞内细菌识别

基本信息

  • 批准号:
    7576802
  • 负责人:
  • 金额:
    $ 28.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-03-01 至 2013-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Intracellular microbial recognition plays a critical role in innate immunity. Small fragments of bacterial peptidoglycan as well as bacterial flagellin are known to stimulate the NOD-like Receptors in mammals. This family of receptors includes both the NOD proteins, which respond to peptidoglycan fragments by activating NF-?B, and the NALP family of proteins, which respond to peptidoglycan, flagellin and other danger signals by activating IL-12 processing and release. Animals deficient in these receptors are hypersusceptible to infection, while humans carrying mutations in NOD2 and NALP3 suffer from autoinflammatory Crohn's disease and Muckle Wells Syndrome. Despite advances, it has not yet been demonstrated that any of these putative intracellular innate immune receptors directly recognize their cognate ligand, nor is it clear how these intracellular receptor transduce signals or how the induced responses contribute to efficient immune protection. In Drosophila, we have recently established that analogous intracellular microbial recognition occurs. Upon injection into flies, small fragments of peptidoglycan are recognized by the intracellular receptor PGRP-LE. Moreover, PGRP-LE directly binds these monomeric fragments of peptidoglycan causing receptor oligomerization. In addition to small fragments of peptidoglycan, PGRP-LE also recognizes cytosolic bacteria, like Listeria monocytogenes, and this recognition is critical to block bacterial growth. These results have led us to hypothesize that PGRP-LE functions as an intracellular receptor capable of recognizing peptidoglycan that enters cells, triggering receptor oligomerization, intracellular signaling and ultimately protective immune responses. We propose a series of 3 Aims that will probe in molecular detail the role of PGRP-LE and intracellular bacterial recognition in producing effective immune responses. Aim 1 will determine which organs, cells and subcellular compartments are involved in the PGRP-LE-mediated response to monomeric peptidoglycan. Aim 2 will characterize the molecular mechanisms of PGRP-LE-mediated signal transduction. The function of ligand-induced receptor oligomerization will be analyzed in vivo; the different responses emanating from intracellular versus cell-surface immune recognition will be probed; and a direct feedback inhibitor of these peptidoglycan binding receptors will be characterized. Aim 3 will analyze the role of PGRP-LE in the response to pathogens that release large quantities of monomeric peptidoglycan. And the role of PGRP-LE in controlling infection by intracellular Listeria monocytogenes will be thoroughly characterized. Autophagy is critical for the control of Listeria and we will determine if PGRP-LE- mediated recognition is required for the induction of this protective response. In people, the innate immune response is absolutely critical for the rapid protection against germs and for the effectiveness of vaccines. In addition, uncontrolled innate immune reactions are often the root cause of auto-inflammatory diseases. Insects, such as the fruit fly, rely entirely on innate immune responses that are very similar to our own innate immune system, and this proposal aims to use the fruit fly, a powerful experimental system, for the study of innate immunity. PUBLIC HEALTH RELEVANCE: In people, the innate immune response is absolutely critical for the rapid protection against germs and for the effectiveness of vaccines. In addition, uncontrolled innate immune reactions are often the root cause of auto-inflammatory diseases. Insects, such as the fruit fly, rely entirely on innate immune responses that are very similar to our own innate immune system, and this proposal aims to use the fruit fly, a powerful experimental system, for the study of innate immunity.
描述(由申请人提供):细胞内微生物识别在先天免疫中起关键作用。已知细菌肽聚糖的小片段以及细菌鞭毛蛋白刺激哺乳动物中的NOD样受体。该受体家族包括NOD蛋白,其通过激活NF-?B和NALP蛋白家族,其通过激活IL-12加工和释放来响应肽聚糖、鞭毛蛋白和其它危险信号。缺乏这些受体的动物对感染高度敏感,而携带NOD 2和NALP 3突变的人患有自身炎症性克罗恩病和Muckle威尔斯综合征。尽管取得了进展,但尚未证明这些推定的细胞内先天免疫受体中的任何一种直接识别其同源配体,也不清楚这些细胞内受体的信号传导或诱导的应答如何有助于有效的免疫保护。在果蝇中,我们最近已经确定,类似的细胞内微生物识别发生。在注射到果蝇中后,肽聚糖的小片段被细胞内受体PGRP-LE识别。此外,PGRP-LE直接结合这些肽聚糖的单体片段,引起受体寡聚化。除了肽聚糖的小片段之外,PGRP-LE还识别胞质细菌,如单核细胞增生李斯特菌,并且这种识别对于阻止细菌生长至关重要。这些结果使我们假设PGRP-LE作为能够识别进入细胞的肽聚糖的细胞内受体起作用,触发受体寡聚化、细胞内信号传导和最终保护性免疫应答。我们提出了一系列的3个目标,将探针在分子细节的作用,PGRP-LE和细胞内的细菌识别产生有效的免疫反应。目的1将确定哪些器官、细胞和亚细胞区室参与PGRP-LE介导的对单体肽聚糖的反应。目的2研究PGRP-LE介导的信号转导的分子机制。将在体内分析配体诱导的受体寡聚化的功能;将探测从细胞内与细胞表面免疫识别产生的不同反应;并表征这些肽聚糖结合受体的直接反馈抑制剂。目的3将分析PGRP-LE在对释放大量单体肽聚糖的病原体的应答中的作用。并且PGRP-LE在控制细胞内单核细胞增生李斯特菌感染中的作用将被彻底表征。自噬对于控制李斯特菌至关重要,我们将确定是否需要PGRP-LE介导的识别来诱导这种保护性反应。在人类中,先天免疫反应对于快速抵御细菌和疫苗的有效性至关重要。此外,不受控制的先天免疫反应通常是自身炎症性疾病的根本原因。昆虫,如果蝇,完全依赖于先天免疫反应,这与我们自己的先天免疫系统非常相似,这项提案旨在利用果蝇这一强大的实验系统来研究先天免疫。 公共卫生关系:在人类中,先天免疫反应对于快速抵御细菌和疫苗的有效性至关重要。此外,不受控制的先天免疫反应通常是自身炎症性疾病的根本原因。昆虫,如果蝇,完全依赖于先天免疫反应,这与我们自己的先天免疫系统非常相似,这项提案旨在利用果蝇这一强大的实验系统来研究先天免疫。

项目成果

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Neal Silverman其他文献

Neal Silverman的其他文献

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{{ truncateString('Neal Silverman', 18)}}的其他基金

Elucidating Leishmania strategies for parasitophorous vacuole biogenesis
阐明利什曼原虫寄生液泡生物发生的策略
  • 批准号:
    10672033
  • 财政年份:
    2022
  • 资助金额:
    $ 28.89万
  • 项目类别:
DNA Virus Infection Induces an Anti-Viral State in Drosophila
DNA病毒感染在果蝇中诱导抗病毒状态
  • 批准号:
    9412809
  • 财政年份:
    2017
  • 资助金额:
    $ 28.89万
  • 项目类别:
Host factors required for Leishmania infection
利什曼原虫感染所需的宿主因素
  • 批准号:
    8639242
  • 财政年份:
    2014
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    10677006
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    8152421
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    8666709
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    9151017
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    8329614
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    10470710
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
Innate Immunity Training Program
先天免疫训练计划
  • 批准号:
    8501351
  • 财政年份:
    2011
  • 资助金额:
    $ 28.89万
  • 项目类别:
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