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
项目总结/文摘:
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:
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:
7655827 - 财政年份:2009
- 资助金额:
$ 58.41万 - 项目类别:
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