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
- 来源:
- 关键词:AddressApoptoticAutomobile DrivingBacteriaBacterial InfectionsBiological ModelsCASP1 geneCASP8 geneCRISPR screenCell DeathCell Death InductionCell MaturationCell membraneCessation of lifeComplexDataDefense MechanismsEventExperimental DesignsExposure toGastroenteritisHost DefenseIL18 geneImmune responseImmune signalingImmunityInfectionInflammasomeInflammationInflammatoryInnate Immune SystemInterleukin-1 betaKnowledgeLinkMAP3K7 geneMacrophageMediatingMediatorMembraneModificationMolecularN-terminalPathogenicityPathologicPathway interactionsPhosphotransferasesPhysiologicalPlaguePlantsPost-Translational Protein ProcessingProcessProteinsRIPK1 geneRoleSignal PathwayStimulusSystemTNF geneType III Secretion System PathwayVirulenceYersiniaYersinia infectionsarms racecytokinecytotoxiccytotoxicityin vivoinnate immune sensingnovelpathogenpathogenic bacteriaresponse
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
项目摘要/摘要:
细菌分泌系统效应物对许多细菌病原体的毒力是必不可少的,而且许多
效应蛋白阻断了关键的免疫信号通路。然而,这些效应器或它们的改变
原因也可以被先天免疫系统感知到。例如,效应器介导的宿主修改
蛋白质可以被识别为病理性的并触发免疫反应,这一过程被称为效应器-
触发豁免(ETI)。虽然ETI最初是在植物中发现的,但现在很明显,ETI是一种常见的防御措施
这一机制是宿主和病原体之间持续不断的军备竞赛的主要驱动因素。知识
关于这些过程是了解细菌毒力和宿主防御的核心。
传统的炎性小体是控制caspase-1和/或11介导的多分子复合体。
嗜热性细胞死亡与炎性细胞因子IL-1b/IL-18的成熟Gasdermin D(GSDMD)为
最近被证明是通过裂解D276残基引发的炎症体下垂的关键介质
Caspase-1/11和释放的N-末端片段在细胞膜上形成一个孔,损害
膜的完整性。这些毛孔还与IL-1β和IL-18的释放有关。巨噬细胞感染
致病性耶尔森氏菌是鼠疫和胃肠炎的病原体,可触发细胞死亡和IL-1β/IL-1。
18释放。我们之前已经描述了一种新的非传统炎症体途径,需要RIP1
激酶和caspase-8,它们通常与凋亡性死亡有关,它们控制细胞因子的释放和
耶尔森氏菌感染后巨噬细胞的细胞毒性。具体来说,III型分泌系统(T3SS)效应器
YopJ强烈激活caspase-8并驱动这一非常规途径。因此,耶尔西尼亚是一个极好的
生理相关的模型系统,以研究caspase-8在细菌感染中的作用。
特别是,我们的支持数据表明,YopJ抑制tak1和ikkcaspase-8激活β-8。
并诱导不依赖于caspase-1或-11的非典型炎症体途径。类似
当抑制TAK1和IKK活性时,可以观察到类似YopJ作用的反应。我们证明了GSDMD
在D276处被裂解,并被耶尔森氏菌以caspase-8依赖方式激活,GSDMD强烈
调节细胞死亡和IL-1β/IL-18的释放。这些发现使我们假设Yersinia YopJ
通过RIPK1和caspase-8触发一种新的效应器介导的免疫反应,导致GSDMD
卵裂、细胞死亡和IL-1β释放。RIPK1和caspase-8是如何激活的,以及这些事件是如何
激活GSDMD是这里要解决的关键问题
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:
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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