The Immune Response to Pathogens is Controlled by the Cytokine-Induced Epigenetics Signature

对病原体的免疫反应由细胞因子诱导的表观遗传学特征控制

基本信息

  • 批准号:
    9526608
  • 负责人:
  • 金额:
    $ 62.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract: A lingering conundrum associated with studying host defense transcription profiles is how do specific cells “remember” whether or not they should be actively transcribing specific genes, which would facilitate their participation in an inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post-translational modifications of histones, as mechanisms to regulate the expression profiles of cell derived mediators during an inflammatory response. We have addressed epigenetic mechanisms that result in the immunopathology caused by influenza, using both normal and infected human cell-based systems and an experimental model of infectious influenza. The latter model will be used to guide our human cell based system. We present data that the cytokine environment established by influenza induces the expression of specific epigenetic machinery that controls the expression of host defense mediators. We identified that interferon beta serves in an autocrine/paracrine manner to cause the expression of Setdb2, an epigenetic- based lysine methyl transferase that is responsible for setting a suppressive histone mark, resulting in host anti-bacterial defense gene silencing. While this sequence of events is likely beneficial against the primary influenza infection, the unintended result is that the defense system that target bacterial infections is impaired. This scenario may provide the mechanism whereby secondary bacterial pneumonia is associated with initial influenza infections. Our data reveals that in both human and mouse models of influenza this same epigenetic pathway can be identified We hypothesize that during the evolution of primary influenza pneumonia a cytokine environment characterized by high levels of IFN-B is established to control the primary viral infection; however, this process engages an epigenetic-based mechanism, which suppresses MΦ pro- inflammatory responses, rendering the host susceptible to secondary bacterial infection. This hypothesis will be investigated via the following specific aims: To determine the mechanism(s) whereby the influenza-induced IFN-B/STAT1 pathway results in the expression of a chromatin modifying lysine methyltransferase, SETDB2, in primary human cells. To investigate a novel mechanism whereby SETDB2 is guided to promoter sites on targeted genes via binding to specific transcription factors, resulting in chromatin modifications at precise promoter locations. To assess the suppressive role of Setdb2 expression on MΦ activity during a primary influenza infection, which decreases both phagocytosis and T cell function and mechanistically contributes to the host susceptibility to secondary bacterial infection. .
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项目成果

期刊论文数量(0)
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Steven Lynn Kunkel其他文献

Steven Lynn Kunkel的其他文献

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{{ truncateString('Steven Lynn Kunkel', 18)}}的其他基金

Research Training in Experimental Immunology
实验免疫学研究培训
  • 批准号:
    9533814
  • 财政年份:
    2016
  • 资助金额:
    $ 62.23万
  • 项目类别:
Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation
慢性肺部炎症期间宿主反应后的细胞因子表型
  • 批准号:
    7578408
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation
慢性肺部炎症期间宿主反应后的细胞因子表型
  • 批准号:
    8197282
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation
慢性肺部炎症期间宿主反应后的细胞因子表型
  • 批准号:
    8387726
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
A multi-scale and multi-system approach to understand granuloma formation in TB
了解结核病肉芽肿形成的多尺度、多系统方法
  • 批准号:
    7498649
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation
慢性肺部炎症期间宿主反应后的细胞因子表型
  • 批准号:
    7993581
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
A multi-scale and multi-system approach to understand granuloma formation in TB
了解结核病肉芽肿形成的多尺度、多系统方法
  • 批准号:
    7877856
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation
慢性肺部炎症期间宿主反应后的细胞因子表型
  • 批准号:
    7743005
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
A multi-scale and multi-system approach to understand granuloma formation in TB
了解结核病肉芽肿形成的多尺度、多系统方法
  • 批准号:
    7659589
  • 财政年份:
    2008
  • 资助金额:
    $ 62.23万
  • 项目类别:
Dynamic Effects of Chemokines on Systematic inflammation
趋化因子对系统炎症的动态影响
  • 批准号:
    7108652
  • 财政年份:
    2005
  • 资助金额:
    $ 62.23万
  • 项目类别:
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