Caspase-8 as a focal hub in effector-triggered immunity

Caspase-8 作为效应子触发免疫的焦点

基本信息

  • 批准号:
    10614514
  • 负责人:
  • 金额:
    $ 58.41万
  • 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:
    2019-05-10 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT: Bacterial secretion system effectors are essential for the virulence of many bacterial pathogens, and a number of effector proteins block key immune signaling pathways. However, these effectors or the alterations they cause can also be sensed by the innate immune system. For example, effector mediated modifications of host proteins can be recognized as pathological and trigger immune responses, a process known as effector- triggered immunity (ETI). While ETI was first discovered in plants, it is now clear that ETI is a common defense mechanism that is a major driving factor in the constant arms race between host and pathogens. Knowledge about these processes is central to understanding bacterial virulence as well as host defense. Conventional inflammasomes are multi-molecular complexes that control caspase-1 and/or 11-mediated pyroptotic cell death and maturation of inflammatory cytokines IL-1b/IL-18. Gasdermin D (GSDMD) was recently shown to be a key mediator of inflammasome triggered pyroptosis by cleavage at residue D276 by caspase-1/11, and the released N-terminal fragments create a pore in cell membranes compromising membrane integrity. These pores are also linked to IL-1β and IL-18 release. Infection of macrophages with pathogenic Yersinia spp., causative agents of plague and gastroenteritis, trigger cell death as well as IL-1β/IL- 18 release. We have previously described a novel unconventional inflammasome pathway, requiring RIP1 kinase and caspase-8, which are typically associated with apoptotic death, that control cytokine release and macrophage cytotoxicity after Yersinia infection. Specifically, the Type III secretion system (T3SS) effector YopJ strongly activates caspase-8 and drives this unconventional pathway. Thus, Yersinia is an excellent physiologically relevant model system to investigate the role of caspase-8 in the context of bacterial infection. In particular, our supporting data indicate that YopJ inhibition of TAK1 and IKKβ kinases activates caspase-8 and induces a non-canonical inflammasome pathway, that is not dependent on caspase-1 or -11. Similar responses are observed when inhibiting TAK1 and IKK activity, mimicking YopJ action. We show that GSDMD is cleaved at D276 and activated by Yersinia in a caspase-8 dependent manner and that GSDMD strongly regulates cell death and IL-1β/IL-18 release. These findings lead us to hypothesize that Yersinia YopJ triggers a novel effector-mediated immune response, via RIPK1 and caspase-8, leading to GSDMD cleavage, cell death and IL-1β release. How RIPK1 and caspase-8 are activated and how these events activate GSDMD are critical questions addressed herein
项目总结/摘要: 细菌分泌系统效应子对于许多细菌病原体的毒力是必需的,并且许多细菌分泌系统效应子对于许多细菌病原体的毒力是必需的。 阻断关键的免疫信号通路。然而,这些效应物或它们的改变, 先天免疫系统也能感觉到病因。例如,效应子介导的宿主修饰 蛋白质可以被认为是病理性的,并触发免疫反应,这一过程被称为效应器, 触发免疫(ETI)。虽然ETI最初是在植物中发现的,但现在很清楚,ETI是一种常见的防御手段。 这一机制是宿主和病原体之间不断军备竞赛的主要驱动因素。知识 了解这些过程是理解细菌毒力和宿主防御的核心。 常规的炎性小体是多分子复合物,其控制半胱天冬酶-1和/或II介导的炎症反应。 炎性细胞死亡和炎性细胞因子IL-1b/IL-18的成熟。Gasdermin D(GSDMD) 最近显示是炎性小体通过在残基D276处切割而触发的焦亡的关键介质, 半胱天冬酶-1/11和释放的N-末端片段在细胞膜中产生孔, 膜完整性这些孔也与IL-1β和IL-18的释放有关。巨噬细胞感染 致病性耶尔森氏菌,鼠疫和胃肠炎的病原体,触发细胞死亡以及IL-1β/IL- 18释放我们之前已经描述了一种新的非常规炎性体途径,需要RIP 1 激酶和半胱天冬酶-8,它们通常与凋亡性死亡相关,控制细胞因子释放, 巨噬细胞的细胞毒性。具体而言,III型分泌系统(T3 SS)效应子 YopJ强烈激活caspase-8并驱动这种非常规途径。因此,耶尔森氏菌是一种优秀的 生理学相关的模型系统来研究胱天蛋白酶-8在细菌感染的情况下的作用。 特别是,我们的支持数据表明,YopJ抑制TAK 1和IKKβ激酶激活caspase-8 并诱导不依赖于半胱天冬酶-1或-11的非典型炎性体途径。类似 当抑制TAK 1和IKK活性时观察到响应,模拟YopJ作用。我们表明,GSDMD 在D276处被切割,并以半胱天冬酶-8依赖性方式被耶尔森氏菌激活, 调节细胞死亡和IL-1β/IL-18释放。这些发现使我们假设耶尔森菌YopJ 通过RIPK 1和caspase-8触发一种新型效应介导的免疫应答,导致GSDMD 裂解、细胞死亡和IL-1β释放。RIPK 1和caspase-8是如何被激活的,以及这些事件是如何发生的 激活GSDMD是本文讨论的关键问题

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Caspase-8 inhibition improves the outcome of bacterial infections in mice by promoting neutrophil activation.
  • DOI:
    10.1016/j.xcrm.2023.101098
  • 发表时间:
    2023-07-18
  • 期刊:
  • 影响因子:
    14.3
  • 作者:
    Lentini, Germana;Fama, Agata;De Gaetano, Giuseppe Valerio;Coppolino, Francesco;Mahjoub, Ahlem Khachroub;Ryan, Liv;Lien, Egil;Espevik, Terje;Beninati, Concetta;Teti, Giuseppe
  • 通讯作者:
    Teti, Giuseppe
MLKL-Driven Inflammasome Activation and Caspase-8 Mediate Inflammatory Cell Death in Influenza A Virus Infection.
  • DOI:
    10.1128/mbio.00110-23
  • 发表时间:
    2023-04-25
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Lei, Xuqiu;Chen, Yongzhi;Lien, Egil;Fitzgerald, Katherine A.
  • 通讯作者:
    Fitzgerald, Katherine A.
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Egil Lien其他文献

Egil Lien的其他文献

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{{ truncateString('Egil Lien', 18)}}的其他基金

Bacterial activation and evasion of a PP2A phosphatase – Pyrin - Gasdermin D axis
PP2A 磷酸酶的细菌激活和逃避 - Pyrin - Gasdermin D 轴
  • 批准号:
    10196593
  • 财政年份:
    2021
  • 资助金额:
    $ 58.41万
  • 项目类别:
Bacterial activation and evasion of a PP2A phosphatase – Pyrin - Gasdermin D axis
PP2A 磷酸酶的细菌激活和逃避 - Pyrin - Gasdermin D 轴
  • 批准号:
    10364690
  • 财政年份:
    2021
  • 资助金额:
    $ 58.41万
  • 项目类别:
Caspase-8 as a focal hub in effector-triggered immunity
Caspase-8 作为效应子触发免疫的焦点
  • 批准号:
    10392961
  • 财政年份:
    2019
  • 资助金额:
    $ 58.41万
  • 项目类别:
Caspase-8 as a focal hub in effector-triggered immunity
Caspase-8 作为效应子触发免疫的焦点
  • 批准号:
    9811189
  • 财政年份:
    2019
  • 资助金额:
    $ 58.41万
  • 项目类别:
Adjuvants and Glucan Particle Vaccines
佐剂和葡聚糖颗粒疫苗
  • 批准号:
    9195714
  • 财政年份:
    2015
  • 资助金额:
    $ 58.41万
  • 项目类别:
The role of LPS-TLR4 signaling in live vaccine-induced protective responses
LPS-TLR4 信号在活疫苗诱导的保护性反应中的作用
  • 批准号:
    8241896
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:
The role of LPS-TLR4 signaling in live vaccine-induced protective responses
LPS-TLR4 信号在活疫苗诱导的保护性反应中的作用
  • 批准号:
    8044810
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:
The role of LPS-TLR4 signaling in live vaccine-induced protective responses
LPS-TLR4 信号在活疫苗诱导的保护性反应中的作用
  • 批准号:
    8441620
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:
The role of LPS-TLR4 signaling in live vaccine-induced protective responses
LPS-TLR4 信号在活疫苗诱导的保护性反应中的作用
  • 批准号:
    7775085
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:
Improving the safety profile of DNA prime - protein boost HIV vaccinations
提高 DNA 初免蛋白增强 HIV 疫苗接种的安全性
  • 批准号:
    7701148
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:

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细胞中激活凋亡半胱天冬酶的生/死决策的机制
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