Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense

明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能

基本信息

  • 批准号:
    10092916
  • 负责人:
  • 金额:
    $ 56.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-01 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

Project Summary Immune defense against bacterial infection requires signaling pathways that activate expression of inflammatory mediators to control and clear infection. Many pathogens inhibit these signaling pathways in order to evade host immune defenses. In particular, Yersinia injects a virulence factor, YopJ, which potently blocks key aspects of NF-ΚB and MAPK signaling pathways. How immune defense is mediated against pathogens that block immune signaling pathways remains poorly understood. NF-κB blockade in macrophages exposed to bacterial PAMPs leads to cell death. Importantly, our recently published data demonstrate that RIPK1 kinase activity is required for Yersinia-induced cell death, and that RIPK1 kinase activity is critical for resistance to Yersinia infection and innate inflammatory cytokine production in vivo. This suggests that RIPK1- induced death triggered by Yersinia is a key immune protective mechanism. Our new studies indicate that IKK phosphorylates RIPK1 to limit induction of cell death by inflammatory stimuli, suggesting that Yersinia blockade of IKK releases RIPK1 from this inhibitory effect. How RIPK1 kinase activity and cell death promote host defense against bacterial infection is not known. Our central hypothesis is that RIPK1-mediated cell death triggered in response to pathogen-mediated NF-κB and MAPK blockade releases pro-inflammatory signals, such as IL-1 cytokines and intracellular alarmins that enable uninfected bystander cells to produce key inflammatory mediators such as TNF, which control infection by pathogens that interfere with innate signaling. This is an important problem as this pathway likely responds to many pathogens that block critical innate immune signaling pathways and in the context of pathological stimuli that lead to RIPK1-induced cell death. We propose three Specific Aims to address this important gap in our knowledge. First we will define the molecular basis for how RIPK1 kinase activation occurs in response to YopJ blockade of IKK signaling, and test the role of this pathway in anti-bacterial immune defense. Second, we will define immune responses of infected and bystander cells, and will define the contribution of RIPK1-dependent cell death pathways to anti- bacterial host defense in vivo. Finally, we will determine the contribution of TNF signaling by bystander cells to antibacterial immune defense and will define the cell-type specific requirement for RIPK1- and TNFR- dependent cell death in host immune defense against Yersinia.
项目摘要 对细菌感染的免疫防御需要激活蛋白表达的信号通路 控制和清除感染的炎性介质。许多病原体抑制这些信号通路。 以逃避宿主的免疫防御。特别是,耶尔西尼亚病毒注入了一种毒力因子YopJ,它能有效地 阻断NF-ΚB和MAPK信号通路的关键方面。免疫防御是如何调节的 阻断免疫信号通路的病原体仍然知之甚少。巨噬细胞内核因子-κB的阻断作用 暴露在细菌PAMPS下会导致细胞死亡。重要的是,我们最近公布的数据表明 RIPK1激酶活性是耶尔森氏菌诱导的细胞死亡所必需的,并且RIPK1激酶活性在 体内对耶尔森氏菌感染的抵抗力和先天炎症细胞因子的产生。这表明RIPK1- 耶尔森氏菌引起的致死是一种重要的免疫保护机制。我们的新研究表明,IKK 磷酸化RIPK1以限制炎症刺激诱导的细胞死亡,表明耶尔森氏菌阻断 从这种抑制作用中释放RIPK1。RIPK1激酶活性和细胞死亡如何促进宿主 针对细菌感染的防御措施尚不清楚。我们的中心假设是RIPK1介导的细胞死亡 病原体介导的NF-κB和MAPK阻断被触发释放促炎信号, 例如IL-1细胞因子和细胞内警报,使未受感染旁观者细胞能够产生 炎性介质,如肿瘤坏死因子,控制干扰先天信号的病原体的感染。 这是一个重要的问题,因为这一途径可能会对许多阻止关键先天的病原体做出反应 免疫信号通路和导致RIPK1诱导细胞死亡的病理刺激的背景下。 我们提出了三个具体目标来解决我们知识中的这一重要差距。首先,我们将定义 RIPK1激活如何在YopJ阻断IKK信号时发生的分子基础,以及 检测该通路在抗细菌免疫防御中的作用。第二,我们将定义免疫反应 感染细胞和旁观者细胞,并将确定依赖RIPK1的细胞死亡途径在抗 体内细菌宿主防御。最后,我们将确定旁观者细胞的肿瘤坏死因子信号对 抗菌免疫防御,并将定义细胞类型对RIPK1-和TNFR-的特定要求 耶尔森氏菌宿主免疫防御中的依赖性细胞死亡。

项目成果

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IGOR E BRODSKY其他文献

IGOR E BRODSKY的其他文献

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{{ truncateString('IGOR E BRODSKY', 18)}}的其他基金

Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis
临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制
  • 批准号:
    10452195
  • 财政年份:
    2022
  • 资助金额:
    $ 56.53万
  • 项目类别:
Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis
临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制
  • 批准号:
    10580079
  • 财政年份:
    2022
  • 资助金额:
    $ 56.53万
  • 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
  • 批准号:
    10329911
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10435528
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10200805
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10649640
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
  • 批准号:
    10557104
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10018488
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Defining the non-apoptotic role of Caspase-8 activity in anti-bacterial immune defense
定义 Caspase-8 活性在抗菌免疫防御中的非凋亡作用
  • 批准号:
    9229681
  • 财政年份:
    2017
  • 资助金额:
    $ 56.53万
  • 项目类别:
Dissecting the mechanism of RIPK1 kinase-dependent cell death in control of Yersinia infection
剖析 RIPK1 激酶依赖性细胞死亡控制耶尔森菌感染的机制
  • 批准号:
    9285729
  • 财政年份:
    2016
  • 资助金额:
    $ 56.53万
  • 项目类别:

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New technologies for targeted delivery of anti-bacterial agents
抗菌药物靶向递送新技术
  • 批准号:
    1654774
  • 财政年份:
    2015
  • 资助金额:
    $ 56.53万
  • 项目类别:
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Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
  • 批准号:
    8416313
  • 财政年份:
    2012
  • 资助金额:
    $ 56.53万
  • 项目类别:
Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
  • 批准号:
    8298885
  • 财政年份:
    2012
  • 资助金额:
    $ 56.53万
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