Immunopathogenesis of Histoplasmosis and TNF
组织胞浆菌病和 TNF 的免疫发病机制
基本信息
- 批准号:10377422
- 负责人:
- 金额:$ 21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Anti-Infective AgentsAnti-Inflammatory AgentsAntifungal AgentsAutomobile DrivingBiologicalBiological ProcessBiologyCD3 AntigensCD4 Positive T LymphocytesCTLA4 geneCell physiologyCellsCellular ImmunityCodeDefectDendritic CellsDevelopmentDiseaseDisinhibitionElementsFOXP3 geneFamilyGenerationsGenesGeneticGlycolysisGranulocyte-Macrophage Colony-Stimulating FactorGrowthHistoplasma capsulatumHistoplasmosisHost DefenseHost resistanceHumanIL2RA geneImmune systemImmunityImmunosuppressive AgentsImpairmentIndividualInfectionInfection ControlInflammationInflammatoryInterferonsInterleukin-10InvestigationLifeLightLinkLungLymphocyte SubsetMetabolicMetabolismMitochondriaMolecularMorbidity - disease rateMusMycobacterium tuberculosisMycosesNatural ImmunityNatureParalysedParasitesPatient CarePatientsPhagocytesPharmaceutical PreparationsPharmacologic SubstancePhenotypePhysiological ProcessesPopulationPreventive therapyProgressive DiseasePropertyRegulatory ElementRegulatory T-LymphocyteRespirationRiskShapesSignal TransductionSuppressor-Effector T-LymphocytesSurfaceT-LymphocyteT-Lymphocyte SubsetsTNF geneTNFRSF1A geneTumor Cell NecrosisUp-RegulationUrsidae FamilyWorkYeastsadaptive immunityantagonistcell typecombatcytokineexperimental studyfightingfrontierfungusimmune functionimmunoregulationimmunosuppressedimprovedin vivoinsightlatent infectionmacrophagemetabolic abnormality assessmentmortalitymouse modelpathogenic fungusprogrammed cell death protein 1pulmonary functionreceptorreceptor expressionrespiratorytranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Description
The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and is
the most frequent cause of respiratory fungal infection. Activation of T cell-mediated immunity is considered to
be a major mechanism for host control of infection. Although most infections are mild, in immunosuppressed
individuals it may become life-threatening. The tumor necrosis factor (TNF)- antagonists are one of the more
common immunosuppressive drugs that undermine immunity and predispose to progressive histoplasmosis.
These agents have improved the lives of many with inflammatory diseases yet put them at risk for disseminat-
ed histoplasmosis. As in humans, neutralization of TNF- in mice disables immunity to the fungus. In infected
mice given anti-TNF-we discovered that conventional lung Foxp3-CD4+ T cells inhibited the ability of IFN--
stimulated M to kill yeast cells. Within this population, we identified the presence of a Foxp3-CD4+CD25- T cell
subset that bears multiple inhibitory receptors including but not limited to PD-1, Tim-3, and TIGIT. We postulate
this T cell subpopulation disarms the growth inhibitory properties of activated macrophages and dendritic cells.
In the first aim we will 1) determine if this subset directly impairs the ability of M stimulated with IFN- or GM-
CSF or dendritic cells to eliminate the fungus; 2) determine if signaling through TNF receptor 1 or 2 is key for
the emergence of this population, and 3) ascertain if these cells negatively regulate immunity in vivo. In the
second aim, we will examine the transcriptome of these cells to identify regulatory elements that prompt the
increased expression of inhibitory receptors. In parallel, we will examine the metabolic properties of these cells
to determine if changes in metabolism may account for the upregulation in inhibitory receptors. We will unite
metabolism with RNA-seq to identify interconnecting networks between metabolism and transcriptomics These
studies will provide new insights into the biology of T cells in the context of TNF- antagonism.
项目描述
致病真菌,组织胞浆菌,是美国中西部和东南部的地方病,
呼吸道真菌感染的最常见原因。T细胞介导的免疫的激活被认为是
是宿主控制感染的主要机制。虽然大多数感染是温和的,在免疫抑制
个人可能会危及生命。肿瘤坏死因子(TNF)-α拮抗剂是目前应用较多的肿瘤坏死因子受体拮抗剂之一。
常见的免疫抑制药物,破坏免疫力,易患组织胞浆菌病。
这些药物改善了许多炎症性疾病患者的生活,但却使他们面临传播的风险。
艾德组织胞浆菌病和人类一样,小鼠中TNF-α的中和作用使其对真菌的免疫力丧失。在受感染
在给予抗-TNF-α的小鼠中,我们发现常规的肺Foxp 3-CD 4 + T细胞抑制IFN-γ的能力。
刺激M细胞杀死酵母细胞。在这个群体中,我们鉴定了Foxp 3-CD 4 + CD 25- T细胞的存在。
在一些实施方案中,抑制性受体是携带多种抑制性受体的亚组,包括但不限于PD-1、Tim-3和TIGIT。我们推测
该T细胞亚群解除了活化的巨噬细胞和树突状细胞的生长抑制特性。
在第一个目标中,我们将1)确定该亚群是否直接损害用IFN-γ或GM刺激的M β的能力,
CSF或树突状细胞以消除真菌; 2)确定通过TNF受体1或2的信号传导是否是
该群体的出现,以及3)确定这些细胞是否在体内负调节免疫。在
第二个目标,我们将检查这些细胞的转录组,以确定促进细胞增殖的调控元件。
抑制性受体表达增加。同时,我们将研究这些细胞的代谢特性,
以确定代谢的变化是否可以解释抑制性受体的上调。我们将团结
代谢与RNA-seq,以确定代谢和转录组学之间的互连网络
这些研究将为TNF-α拮抗作用背景下的T细胞生物学提供新的见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('GEORGE S. DEEPE', 18)}}的其他基金
Immunopathogenesis of Histoplasmosis and TNF
组织胞浆菌病和 TNF 的免疫发病机制
- 批准号:
10227274 - 财政年份:2021
- 资助金额:
$ 21万 - 项目类别:
Dendritic cell KLF2/Notch Axis and Th2 Responses to Eukaryotic Pathogens
树突状细胞 KLF2/Notch 轴和 Th2 对真核病原体的反应
- 批准号:
9195249 - 财政年份:2016
- 资助金额:
$ 21万 - 项目类别:
Dendritic cell KLF2/Notch Axis and Th2 Responses to Eukaryotic Pathogens
树突状细胞 KLF2/Notch 轴和 Th2 对真核病原体的反应
- 批准号:
9293248 - 财政年份:2016
- 资助金额:
$ 21万 - 项目类别:
GM-CSF-Induced Metal Sequestration and Histoplasma
GM-CSF 诱导的金属螯合和组织胞浆菌
- 批准号:
10437747 - 财政年份:2013
- 资助金额:
$ 21万 - 项目类别:
GM-CSF-Induced Metal Sequestration and Histoplasma
GM-CSF 诱导的金属螯合和组织胞浆菌
- 批准号:
9042231 - 财政年份:2013
- 资助金额:
$ 21万 - 项目类别:
GM-CSF-Induced Metal Sequestration and Histoplasma
GM-CSF 诱导的金属螯合和组织胞浆菌
- 批准号:
9256435 - 财政年份:2013
- 资助金额:
$ 21万 - 项目类别:
GM-CSF-Induced Metal Sequestration and Histoplasma
GM-CSF 诱导的金属螯合和组织胞浆菌
- 批准号:
8598633 - 财政年份:2013
- 资助金额:
$ 21万 - 项目类别:
GM-CSF-Induced Metal Sequestration and Histoplasma
GM-CSF 诱导的金属螯合和组织胞浆菌
- 批准号:
10189487 - 财政年份:2013
- 资助金额:
$ 21万 - 项目类别:
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