Role of caspase-8 in innate immunity to infection
Role of caspase-8 in innate immunity to infection
批准号:
10331886
负责人:
Melissa Bruckner Lodoen
金额:
$18.14万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-22 至 2024-12-31
关键词:
AcuteBindingBiotinBlood CellsCASP1 geneCASP8 and FADD-like apoptosis regulating proteinCASP8 geneCaspaseCell DeathCellsChemical EngineeringDataDiseaseGeneticGenetic TranscriptionGoalsHost DefenseHumanImmuneImmune responseImpairmentIndividualInfectionInflammasomeInflammationInflammatoryInflammatory ResponseKnock-outLengthMediatingMicroscopyModelingMolecularMusMyeloid CellsNF-kappa BNatural ImmunityParasitesPathway interactionsPattern recognition receptorPeptide HydrolasesPharmacologyPlayPrecipitationPrimary InfectionProcessProductionProteolytic ProcessingRIPK1 geneRIPK3 geneRegulationReportingResearchResolutionRoleSignal TransductionTherapeuticToll-like receptor 11Toll-like receptorsToxoplasma gondiiToxoplasmosisbasecytokineglobal healthhuman pathogenimmune activationinhibitorinnate immune pathwaysmacrophagemonocyteperipheral bloodpreventrecruitresponsetherapeutic developmenttissue injurytraffickingvesicle transportvesicular release
中文摘要
项目摘要
虽然炎症反应在控制感染中起关键作用,但失调的炎症反应是一个重要的因素。
与炎症和免疫介导的疾病有关。IL-1b是一种细胞因子,
作为炎症的引发剂,以及髓样细胞合成和释放IL-1b的途径,
被描述。在经典的活化途径中,通过Toll样受体(TLR)的信号触发NF-κ B
IL-1b前体被蛋白水解切割成成熟的生物活性IL-1b,
caspase-1在炎性小体中发挥作用。该途径在小鼠巨噬细胞中得到最好的表征。
然而,有趣的是,人类细胞调节炎性小体的方式与小鼠细胞不同,
对于这些炎症途径中功能差异的分子基础了解相对较少。
我研究的长期目标是确定人类先天免疫的分子机制,
感染细胞内的原生动物寄生虫弓形虫。虽然T.弓形虫感染估计
全世界三分之一的人,并导致致命的疾病,免疫功能低下的个人,相对较少,
已知人类先天识别寄生虫,因为识别T。小鼠弓形虫
(TLR 11/TLR 12)在人类细胞中不起作用。我们最近报道,感染人类外周血
血单核细胞T.弓形虫通过Syk-CARD 9-NF-kB信号传导和NLRP 3导致IL-1b释放
炎性小体激活。在使用基因敲除细胞和药理学抑制剂的初步研究中,
我们发现caspase-8缺陷导致T.感染弓形虫的人
单核细胞我们推测caspase-8参与了炎性小体下游IL-1b的释放,
激活T.人单核细胞的弓形虫感染。半胱天冬酶-8对炎症和单核细胞至关重要-
介导的宿主防御T.小鼠弓形虫感染然而,目前还不清楚caspase-8在细胞内的作用机制。
T.人单核细胞的弓形虫感染。这项建议的目的是
确定caspase-8在调节T.感染了刚第虫的人单核细胞
这项研究意义重大,因为人类免疫细胞中的炎症途径相对较差
定义,并且理解这些过程可能有助于开发治疗剂以调节或
抑制炎症。在目的1中,我们将确定caspase-8在感染的细胞释放IL-1b中的作用,
单核细胞在目标2中,我们将定义caspase-8活性的功能要求,包括其加工
以及与细胞伴侣的联系。弓形虫感染这项提议试图破译
在T.人单核细胞的弓形虫感染,并将有助于
定义响应全球健康人类病原体感染而激活的先天免疫途径
重要性
英文摘要
PROJECT SUMMARY
Although inflammatory responses play a key role in controlling infection, dysregulated inflammation is
associated with inflammatory and immune-mediated diseases. IL-1b is a cytokine that functions in host
defense as an initiator of inflammation, and the pathways of IL-1b synthesis and release by myeloid cells have
been described. In the classical pathway of activation, signals through Toll-like receptors (TLRs) trigger NF-kB
activation and IL-1b transcription, and pro-IL-1b is proteolytically cleaved to mature, bioactive IL-1b by
caspase-1 functioning in the inflammasome. This pathway is best characterized in mouse macrophages.
Interestingly, however, human cells regulate the inflammasome differently than mouse cells, and the
molecular basis for the functional differences in these inflammatory pathways are relatively poorly understood.
The long-term goal of my research is to define molecular mechanisms of human innate immunity during
infection with the intracellular protozoan parasite Toxoplasma gondii. Although T. gondii infects an estimated
one-third of humans worldwide and causes fatal disease in immune-compromised individuals, relatively little is
known about human innate recognition of the parasite, since the TLRs that recognize T. gondii in mice
(TLR11/TLR12) are not functional in human cells. We recently reported that infection of human peripheral
blood monocytes with T. gondii results in IL-1b release via Syk-CARD9-NF-kB signaling and NLRP3
inflammasome activation. In preliminary studies using genetic knockout cells and pharmacological inhibitors,
we found that caspase-8 deficiency resulted in reduced IL-1b release from T. gondii-infected human
monocytes. We hypothesize that caspase-8 is involved in IL-1b release downstream of inflammasome
activation during T. gondii infection of human monocytes. Caspase-8 is critical for inflammation and monocyte-
mediated host defense against T. gondii in mice. However, it remains unknown how caspase-8 functions in
inflammatory pathways during T. gondii infection of human monocytes. The objective of this proposal is to
determine the role of caspase-8 in the regulation of IL-1b release from T. gondii-infected human monocytes.
This research is significant because pathways of inflammation in human immune cells are relatively poorly
defined, and understanding these processes may contribute to efforts to develop therapeutics to modulate or
dampen inflammation. In Aim 1, we will determine the role of caspase-8 in IL-1b release from infected
monocytes. In Aim 2, we will define the functional requirements of caspase-8 activity, including its processing
and association with cellular partners, during T. gondii infection. This proposal seeks to decipher the molecular
determinants of inflammatory signaling during T. gondii infection of human monocytes and will contribute to
defining innate immune pathways activated in response to infection with a human pathogen of global health
importance.
期刊论文(0)
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会议论文
Neuroinflammation during cerebral Toxoplasma gondii infection
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批准号:10258923
-
项目类别:
-
资助金额:$21.76万
-
财政年份:2021
-
负责人:Melissa Bruckner Lodoen
-
依托单位:
Neuroinflammation during cerebral Toxoplasma gondii infection
-
批准号:10374176
-
项目类别:
-
资助金额:$17.77万
-
财政年份:2021
-
负责人:Melissa Bruckner Lodoen
-
依托单位:
Parasite dissemination in Toxoplasmic encephalitis
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批准号:9889871
-
项目类别:
-
资助金额:$38.63万
-
财政年份:2016
-
负责人:Melissa Bruckner Lodoen
-
依托单位:
Mechanisms of Toxoplasma gondii dissemination and transmigration
-
批准号:8893191
-
项目类别:
-
资助金额:$36.89万
-
财政年份:2014
-
负责人:Melissa Bruckner Lodoen
-
依托单位:
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