Molecular Mechanisms of Type I IFN Induction during Chlamydia Infection

衣原体感染过程中 I 型干扰素诱导的分子机制

基本信息

  • 批准号:
    8825397
  • 负责人:
  • 金额:
    $ 38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-06-03 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Chlamydia trachomatis genital infection is a major cause of pelvic inflammatory disease (PID), resulting in ectopic pregnancy and infertility among women. PID is caused by an overt inflammatory response in the upper genital tract. The specific immune mechanisms and effectors that trigger this often-devastating condition are poorly defined. The mouse model is a useful tool to study these inflammatory responses in the oviduct. Using this model, we have shown that signaling from the host receptors IFNAR (IFNa/b receptor) and IL-1R (IL-1 receptor) leads to oviduct pathology during genital chlamydial infection. However, the exact mechanisms by which chlamydiae initiate these responses, and the host molecules engaged, are unknown. The central hypothesis of this application is that type I IFN and IL-1 signaling synergistically drive oviduct damage during infection by activating cell death pathways and increasing PMN infiltration. Our overall objectives are to (1) delineate the upstream activators and downstream effectors of IFN and IL-1R signaling which lead to pathology, and (2) therapeutically block the downstream mediators of IL-1R signaling-induced oviduct damage, using the mouse model. To test our hypothesis and achieve our objectives, we will identify the specific molecular interaction between host DNA sensor and chlamydial effector that initiate IFNb expression during infection (Aim 1). We will test the hypothesis that caspase-11 mediated cell death activation is a major player in pathology and type I IFN signaling results in caspase-11 activation during infection (Aim 2). We will explore the role of damage associated molecular patterns (DAMPs), such as HMGB-1 and IL-1a present in genital secretions of infected mice, in oviduct pathology (Aim 3). We also propose to specifically target the damaging arm of IL-1R signaling using inhibitors in ex vivo Fallopian tube explants and in the mouse model to protect from pathology (Aim 4). The central theme of this application is that these signaling events likely evolved to reduce pathogen load in the oviduct, but lead to cell death and tissue damage, thereby come at an expense of adverse reproductive health in women. Delineating the innate immune pathways to segregate the damaging and protective constituents, facilitates therapeutic targeting to prevent disease without affecting resolution of infection. Specific outcomes of the proposed study include identification of host molecules involved in amplification of the inflammatory response during infection, which would serve as biomarkers and therapeutic targets to prevent reproductive sequelae in women infected with Chlamydia.
描述(由申请人提供):沙眼衣原体生殖器感染是盆腔炎(PID)的主要原因,导致异位妊娠和不孕症的妇女。PID是由上生殖道的明显炎症反应引起的。触发这种通常具有破坏性的疾病的特定免疫机制和效应器定义不清。小鼠模型是研究输卵管中这些炎症反应的有用工具。使用该模型,我们已经表明,来自宿主受体IFNAR(IFNa/B受体)和IL-1 R(IL-1受体)的信号传导导致生殖器衣原体感染期间的输卵管病理。然而,衣原体启动这些反应的确切机制以及参与的宿主分子尚不清楚。本申请的中心假设是I型IFN和IL-1信号传导通过激活细胞死亡途径和增加PMN浸润协同驱动感染期间的输卵管损伤。我们的总体目标是(1)描述导致病理的IFN和IL-1 R信号传导的上游激活物和下游效应物,和(2)使用小鼠模型治疗性阻断IL-1 R信号传导诱导的输卵管损伤的下游介质。为了验证我们的假设并实现我们的目标,我们将鉴定宿主DNA传感器和衣原体效应子之间在感染期间启动IFNb表达的特异性分子相互作用(目的1)。我们将检验这样的假设,即半胱天冬酶-11介导的细胞死亡激活是病理学中的主要参与者,并且I型IFN信号传导导致感染期间半胱天冬酶-11激活(目的2)。我们将探讨损伤相关分子模式(DAMP),如HMGB-1和IL-1a存在于感染小鼠的生殖器分泌物中,在输卵管病理学中的作用(目的3)。我们还提出在离体输卵管外植体和小鼠模型中使用抑制剂特异性靶向IL-1 R信号传导的破坏性臂,以防止病理(目的4)。本申请的中心主题是,这些信号传导事件可能进化为减少输卵管中的病原体负荷,但导致细胞死亡和组织损伤,从而以女性的不良生殖健康为代价。描述先天免疫途径以分离破坏性和保护性成分,促进治疗靶向以预防疾病而不影响感染的消退。拟议研究的具体结果包括鉴定感染期间参与炎症反应放大的宿主分子,这些分子将作为生物标志物和治疗靶点,以预防感染衣原体的女性的生殖后遗症。

项目成果

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Uma M Nagarajan其他文献

Uma M Nagarajan的其他文献

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{{ truncateString('Uma M Nagarajan', 18)}}的其他基金

IRF3 is a novel mediator of cell death during genital Chlamydia infection.
IRF3 是生殖器衣原体感染期间细胞死亡的新型介质。
  • 批准号:
    9092280
  • 财政年份:
    2016
  • 资助金额:
    $ 38万
  • 项目类别:
IRF3 is a novel mediator of cell death during genital Chlamydia infection.
IRF3 是生殖器衣原体感染期间细胞死亡的新型介质。
  • 批准号:
    9310325
  • 财政年份:
    2016
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
  • 批准号:
    7876686
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
  • 批准号:
    8434975
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
  • 批准号:
    7627936
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
  • 批准号:
    7425070
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
  • 批准号:
    7263821
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular Mechanisms of Type I IFN Induction during Chlamydia Infection
衣原体感染过程中 I 型干扰素诱导的分子机制
  • 批准号:
    8695757
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
  • 批准号:
    8067122
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:

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