Re-educating T cell-mediated immunity in SIV by modulating metabolic pathways
通过调节代谢途径重新训练 SIV 中 T 细胞介导的免疫
基本信息
- 批准号:10481246
- 负责人:
- 金额:$ 19.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAffectAnatomyAnimalsAntigensAutopsyBacillusBiological AssayBloodCD8-Positive T-LymphocytesCell SurvivalCell physiologyCellsCellular ImmunityCellular Indexing of Transcriptomes and Epitopes by SequencingCellular Metabolic ProcessChronicCommunicable DiseasesComplexDisease ProgressionEnergy MetabolismEnvironmentExhibitsFDA approvedFatty AcidsFlow CytometryGenus HippocampusGlycolysisGoalsHIVHIV AntigensHIV InfectionsHIV/TBHost DefenseHumanImmuneImmunityImmunologicsImpairmentIndividualInfectionInvestigationMacaca fascicularisMeasuresMediatingMetabolicMetabolic PathwayMetabolismMetforminMitochondriaModalityModelingMonitorMycobacterium tuberculosisOpportunistic InfectionsOxidative PhosphorylationPET/CT scanPathologyPathway interactionsPatientsPeptidesPeripheralPersonsPharmaceutical PreparationsPhenotypePlasmaPlayPredispositionPrevalenceProcessRoleSIVSamplingSignal TransductionStressT-LymphocyteTestingTimeTissuesTuberculosisViral Load resultViral reservoirVirus DiseasesX-Ray Computed Tomographyantiretroviral therapyco-infectionexhaustexhaustionglobal healthimmune activationimprovedlymph nodesnonhuman primateoxidationpathogenprogrammed cell death protein 1programsreceptorresponsesingle-cell RNA sequencingtooluptake
项目摘要
Project Summary/Abstract
HIV/AIDS is a chronic infectious disease that affects around 37 million people worldwide. CD8 T cells play a
critical role in controlling HIV infection. However, CD8 T cells become exhausted over time due to continuous
stimulation. Exhausted HIV-specific CD8 T cells, characterized by elevated expression of inhibitory receptors
(e.g. PD-1), positively correlate with higher viral load, impaired T cell function, and disease progression. In HIV
and other chronic viral infections, exhausted antigen-specific CD8 T cells expressing PD-1 can create a
suppressive environment suggesting that such cells not only have a direct role in disease progression but can
cross-talk with other immune cells to impair their function. Chronic HIV infection dysregulates T cell energy
metabolism. HIV-specific CD8 T cells isolated from infected individuals exhibit elevated mitochondrial stress
which is still apparent years after antiretroviral therapy (ART). PD-1 expression on T cells is associated with
mitochondrial stress. PD-1-mediated signaling dysregulates T cell mitochondrial energetics by reducing
glycolysis and shifting towards fatty acid b-oxidation and oxidative phosphorylation (OxPhos). Metformin is an
FDA-approved drug that dampens OxPhos by inhibiting mitochondrial complex I. To date, most studies
investigating metformin use in HIV+ individuals are often in the presence of ART. It has yet to be explored how
modulating energy metabolism with metformin impacts host immunity in an ART-naïve setting. HIV not only
impairs immune control of the viral infection, but also increases susceptibility to opportunistic infections. People
living with HIV are incredibly susceptible to the tuberculosis-causing bacilli, Mycobacterium tuberculosis (Mtb).
We previously showed SIV-infected Mauritian cynomolgus macaques (MCM) to be more susceptible to Mtb,
which we attributed to immunologic impairment by preexisting SIV infection. Therefore, Mtb challenge is a
stringent assessment of host defenses and, given the prevalence of HIV/Mtb co-infection, has great relevance
to global health.
In this K01 proposal, we will identify pathways involved in energy metabolism in CD8 T cells during chronic HIV
infection and reveal their role in T cell exhaustion using our established MCM model of HIV. We will use a
comprehensive analytic approach that combines single cell RNA sequencing, metabolic assays, and flow
cytometry to assess the role of T cell metabolism in SIV-infected MCM. We will alter metabolism using metformin
to reprogram CD8 T cells and determine whether this metabolic reprogramming improves host immunity by
challenging SIV+ animals with Mtb.
项目概要/摘要
HIV/艾滋病是一种慢性传染病,影响着全世界约 3700 万人。 CD8 T 细胞发挥
在控制艾滋病毒感染方面发挥着重要作用。然而,随着时间的推移,CD8 T 细胞会因持续的
刺激。 HIV 特异性 CD8 T 细胞耗尽,其特征是抑制性受体表达升高
(例如 PD-1)与较高的病毒载量、受损的 T 细胞功能和疾病进展呈正相关。在艾滋病毒中
和其他慢性病毒感染时,表达 PD-1 的耗尽的抗原特异性 CD8 T 细胞可以产生
抑制环境表明这些细胞不仅在疾病进展中具有直接作用,而且可以
与其他免疫细胞串扰,损害其功能。慢性 HIV 感染导致 T 细胞能量失调
代谢。从感染个体中分离出的 HIV 特异性 CD8 T 细胞表现出线粒体应激升高
在抗逆转录病毒治疗(ART)多年后,这种现象仍然很明显。 T 细胞上的 PD-1 表达与
线粒体应激。 PD-1介导的信号传导通过减少T细胞线粒体能量失调
糖酵解并转向脂肪酸 b-氧化和氧化磷酸化 (OxPhos)。二甲双胍是一种
FDA 批准的药物通过抑制线粒体复合物 I 来抑制 OxPhos。迄今为止,大多数研究
研究 HIV+ 个体中二甲双胍的使用情况通常是在 ART 存在的情况下进行的。如何进行还有待探讨
在未接受 ART 的环境中,用二甲双胍调节能量代谢会影响宿主的免疫力。艾滋病不仅
损害病毒感染的免疫控制,但也会增加对机会性感染的易感性。人们
艾滋病毒感染者非常容易受到引起结核病的结核杆菌(Mtb)的影响。
我们之前表明感染 SIV 的毛里求斯食蟹猴 (MCM) 更容易感染 Mtb,
我们将其归因于先前存在的 SIV 感染导致的免疫损伤。因此,Mtb 挑战是
鉴于 HIV/Mtb 混合感染的流行,对宿主防御的严格评估具有很大的相关性
为了全球健康。
在这个 K01 提案中,我们将确定慢性 HIV 期间 CD8 T 细胞能量代谢的相关途径
感染并使用我们建立的 HIV MCM 模型揭示其在 T 细胞耗竭中的作用。我们将使用一个
综合分析方法,结合了单细胞 RNA 测序、代谢测定和流式细胞术
细胞计数法评估 T 细胞代谢在 SIV 感染的 MCM 中的作用。我们将使用二甲双胍改变新陈代谢
重新编程 CD8 T 细胞并确定这种代谢重新编程是否可以通过以下方式改善宿主免疫力:
用 Mtb 挑战 SIV+ 动物。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ERICA CHRISTINE LARSON其他文献
ERICA CHRISTINE LARSON的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ERICA CHRISTINE LARSON', 18)}}的其他基金
Re-educating T cell-mediated immunity in SIV by modulating metabolic pathways
通过调节代谢途径重新训练 SIV 中 T 细胞介导的免疫
- 批准号:
10596151 - 财政年份:2022
- 资助金额:
$ 19.13万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 19.13万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 19.13万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 19.13万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 19.13万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




