Innate immune-mediated control of pulmonary Legionella pneumophila infection

先天免疫介导控制肺部嗜肺军团菌感染

基本信息

  • 批准号:
    10867793
  • 负责人:
  • 金额:
    $ 8.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-11-16 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary Intracellular bacterial pathogens such as Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, are responsible for significant morbidity and mortality worldwide. As the spread of broad-spectrum antibiotic resistance among bacterial pathogens is escalating, discovery of novel innate immune defense mechanisms may hold the key for future therapeutic approaches to deal with this increasing threat. Intracellular pathogens deploy virulence factors to disable many immune cell functions. To win this battle, the host must overcome this subversion, through as yet poorly defined mechanisms. To address this critical gap in knowledge, we seek to define the parameters of successful innate immune clearance of Legionella. Legionella replicates within alveolar macrophages by using its type IV secretion system to deliver bacterial effectors, several of which inhibit host protein synthesis. Several effectors inhibit host protein synthesis. Despite this block in host translation, Legionella infection paradoxically enhances production of inflammatory cytokines. In the previous funding period, we demonstrated that Legionella-infected alveolar macrophages are able to synthesize and release IL-1; moreover, IL-1 receptor (IL-1R) signaling was required for robust production of TNF and IL-12 by bystander myeloid cells. Intriguingly, our newly published study show for the first time that IL-1R signaling in alveolar epithelial cells induces production of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was required for bystander cytokine production and bacterial clearance. Intriguingly, while GM-CSF acts as a potent inflammatory cytokine in host defense against a broad spectrum of pathogens, our findings show for the first time that GM-CSF metabolically reprograms monocytes to undergo aerobic glycolysis, thereby promoting cytokine production. We will test the hypothesis that alveolar epithelium-derived GM-CSF metabolically reprograms monocytes to amplify epigenetic changes that enhance TLR-driven cytokine production and control of infection. In this renewal, we propose three Aims to first: define which cell types produce and respond to GM-CSF, second: understand the role of GM-CSF-mediated metabolic reprogramming in host defense, and third: define how GM-CSF and TLR signaling collaborate to promote cytokine production. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.
项目总结

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Listening In: Plasmacytoid DC, Monocyte-Derived DC, and Neutrophil Crosstalk in Antifungal Defense.
  • DOI:
    10.1016/j.chom.2020.06.015
  • 发表时间:
    2020-07-08
  • 期刊:
  • 影响因子:
    30.3
  • 作者:
    Liu, Xin;Shin, Sunny
  • 通讯作者:
    Shin, Sunny
Viewing Legionella pneumophila Pathogenesis through an Immunological Lens.
  • DOI:
    10.1016/j.jmb.2019.07.028
  • 发表时间:
    2019-10-04
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Liu, Xin;Shin, Sunny
  • 通讯作者:
    Shin, Sunny
TNF and type I IFN induction of the IRG1-itaconate pathway restricts Coxiella burnetii replication within mouse macrophages.
IRG1-衣康酸途径的 TNF 和 I 型 IFN 诱导限制了小鼠巨噬细胞内伯氏柯克斯体的复制。
Legionella-Infected Macrophages Engage the Alveolar Epithelium to Metabolically Reprogram Myeloid Cells and Promote Antibacterial Inflammation.
  • DOI:
    10.1016/j.chom.2020.07.019
  • 发表时间:
    2020-11-11
  • 期刊:
  • 影响因子:
    30.3
  • 作者:
    Liu, Xin;Boyer, Mark A.;Holmgren, Alicia M.;Shin, Sunny
  • 通讯作者:
    Shin, Sunny
Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity.
  • DOI:
    10.1371/journal.ppat.1006785
  • 发表时间:
    2017-12
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Mantegazza AR;Wynosky-Dolfi MA;Casson CN;Lefkovith AJ;Shin S;Brodsky IE;Marks MS
  • 通讯作者:
    Marks MS
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Sunny Shin其他文献

Sunny Shin的其他文献

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{{ truncateString('Sunny Shin', 18)}}的其他基金

Effector-triggered immunity against Legionella pneumophila in dendritic cells
树突状细胞中针对嗜肺军团菌的效应子触发免疫
  • 批准号:
    10753211
  • 财政年份:
    2023
  • 资助金额:
    $ 8.15万
  • 项目类别:
TNF and caspase-8-mediated control of Legionella pneumophila infection
TNF 和 caspase-8 介导的嗜肺军团菌感染控制
  • 批准号:
    10364637
  • 财政年份:
    2021
  • 资助金额:
    $ 8.15万
  • 项目类别:
Defining human noncanonical inflammasome responses to Legionella pneumophila
定义人类对嗜肺军团菌的非典型炎症反应
  • 批准号:
    9214308
  • 财政年份:
    2016
  • 资助金额:
    $ 8.15万
  • 项目类别:
Defining human noncanonical inflammasome responses to Legionella pneumophila
定义人类对嗜肺军团菌的非典型炎症反应
  • 批准号:
    9079707
  • 财政年份:
    2016
  • 资助金额:
    $ 8.15万
  • 项目类别:
Innate immune-mediated control of pulmonary Legionella pneumophila infection
先天免疫介导控制肺部嗜肺军团菌感染
  • 批准号:
    10675707
  • 财政年份:
    2015
  • 资助金额:
    $ 8.15万
  • 项目类别:
Innate immune-mediated control of pulmonary Legionella pneumophila infection
先天免疫介导控制肺部嗜肺军团菌感染
  • 批准号:
    9180679
  • 财政年份:
    2015
  • 资助金额:
    $ 8.15万
  • 项目类别:
Innate immune-mediated control of pulmonary Legionella pneumophila infection
先天免疫介导控制肺部嗜肺军团菌感染
  • 批准号:
    9378776
  • 财政年份:
    2015
  • 资助金额:
    $ 8.15万
  • 项目类别:
Innate immune-mediated control of pulmonary Legionella pneumophila infection
先天免疫介导控制肺部嗜肺军团菌感染
  • 批准号:
    9052504
  • 财政年份:
    2015
  • 资助金额:
    $ 8.15万
  • 项目类别:
Innate immune-mediated control of pulmonary Legionella pneumophila infection
先天免疫介导控制肺部嗜肺军团菌感染
  • 批准号:
    10437007
  • 财政年份:
    2015
  • 资助金额:
    $ 8.15万
  • 项目类别:
Innate immune-mediated control of pulmonary Legionella pneumophila infection
先天免疫介导控制肺部嗜肺军团菌感染
  • 批准号:
    10317640
  • 财政年份:
    2015
  • 资助金额:
    $ 8.15万
  • 项目类别:

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