Gender difference in miRNA-mediated T cell aging during viral infection
病毒感染期间 miRNA 介导的 T 细胞衰老的性别差异
基本信息
- 批准号:9896225
- 负责人:
- 金额:$ 9.62万
- 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:2019-06-17 至 2020-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Hepatitis CAffectAfrican AmericanAgeAgingBiological AssayCD28 geneCD3 AntigensCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell AgingCell physiologyCellsCharacteristicsChronic Hepatitis CDiseaseExhibitsFc ReceptorFemaleFunctional disorderGenderGenesGenotypeGoalsHepatitis CHepatitis C virusHumanImmune responseImmunityImpairmentIndividualInfectionKiller CellsLectinMediatingMicroRNAsModelingNatural HistoryOutcomePatientsPhosphoric Monoester HydrolasesPlayRaceReceptor ActivationReceptor SignalingRegulationRoleSignal TransductionT cell regulationT cell responseT-Cell ReceptorT-LymphocyteTestingTimeTranslatingTranslationsUp-RegulationVariantViralViral AntigensViral Load resultVirusVirus Diseasesbasecaucasian Americanchronic infectiongender differenceimmunological statusimprovedloss of functionmalememberprematureracial differencereceptorresponsetranslational approach
项目摘要
Major racial and gender differences have been recognized in the natural history of hepatitis C virus (HCV)
infection; however, the underlying mechanism for this phenomenon remain poorly understood. In studying the
natural history of HCV infection, it has been well-recognized that i) white females have an 8-fold greater chance
of spontaneous viral clearance of acute HCV infection; ii) African American (AA) males with genotype 1 HCV
infection have higher rates of viral persistence or chronic infection than Caucasian Americans (CA); and iii) these
differences are not explained by the baseline viral loads, genotypes, or disease characteristics, but related to
the host immune status, in particular T cell responses. In studying the effect of viral infection on T cell functions,
we and others have recently found that chronic HCV infection leads to T cell dysfunction mediated through up-
regulation of aging markers, including killer cell lectin-like receptor subfamily G member 1 (KLRG1) and dual
specific phosphatase 6 (DUSP6), concomitant with a decline of microRNA-181a (miR181) levels in CD4 T cells.
These observations suggest that the inability of host to clear virus during chronic infection may be a result of
microRNA-mediated impairment of host immunity, and that race/gender influences on the natural history of HCV
infection may be due to a difference in virus-induced, miRNA-mediated signaling. Indeed, with increasing age,
KLRG1 is up-regulated and leads to inhibition of T cell receptor (TCR) signaling, whereas DUSP6 is increased
and leads to recalibration of the TCR activation threshold; miR181 declines to permit translation of a set of genes
related to T cell inhibition. However, the mechanisms underlying miR181/KLRG1/DUSP6 expression and
regulation of premature T cell aging during HCV infection and their relationships to the gender difference in the
natural history of HCV infection remain unclear. We thus hypothesize that virus-induced microRNAs may
exhibit a gender difference, which may affect T cell responses that contribute to the natural history of
HCV infection. To test this hypothesis, we will carry out the following specific aims: 1) Does HCV induce a
different level of miR181, resulting in different T cell responses from male and female HCV-infected or HCV-
resolved patients? 2) Are there any differences in miR181 expression in CD4 and CD8 T cells from male and
female healthy subjects in response to stimulation by TCR antibodies (anti-CD3/CD28) or HCV antigens? 3)
What is the role of HCV-mediated miR181 on host immune responses by gain- or loss-of-function assays,
including virus-specific T cell responses? The overall goal of this supplemental proposal is to employ a
translational approach to obtain a unified overview on whether HCV may induce different levels of miR181 in T
cells from male and female subjects, which may translate into different levels of host T cell responses, and thus
contribute to different outcomes of HCV infection.
丙型肝炎病毒 (HCV) 的自然史已认识到主要的种族和性别差异
感染;然而,人们对这种现象的根本机制仍知之甚少。在学习中
HCV 感染的自然史,人们普遍认识到 i) 白人女性的感染机会高出 8 倍
急性 HCV 感染的自发病毒清除; ii) 具有基因型 1 HCV 的非裔美国人 (AA) 男性
感染者的病毒持续性或慢性感染率高于白人美国人 (CA); iii) 这些
差异不能用基线病毒载量、基因型或疾病特征来解释,而是与
宿主免疫状态,特别是 T 细胞反应。在研究病毒感染对 T 细胞功能的影响时,
我们和其他人最近发现,慢性 HCV 感染会导致 T 细胞功能障碍,这是通过上行介导的
衰老标志物的调节,包括杀伤细胞凝集素样受体亚家族 G 成员 1 (KLRG1) 和双重
特异性磷酸酶 6 (DUSP6),同时 CD4 T 细胞中 microRNA-181a (miR181) 水平下降。
这些观察结果表明,宿主在慢性感染期间无法清除病毒可能是由于
microRNA 介导的宿主免疫损伤,以及种族/性别对 HCV 自然史的影响
感染可能是由于病毒诱导、miRNA 介导的信号传导存在差异所致。确实,随着年龄的增长,
KLRG1 上调并导致 T 细胞受体 (TCR) 信号传导抑制,而 DUSP6 上调
并导致 TCR 激活阈值的重新校准; miR181 拒绝翻译一组基因
与T细胞抑制有关。然而,miR181/KLRG1/DUSP6 表达的潜在机制和
HCV感染过程中T细胞过早衰老的调控及其与性别差异的关系
HCV 感染的自然史仍不清楚。因此,我们假设病毒诱导的 microRNA 可能
表现出性别差异,这可能会影响 T 细胞反应,而 T 细胞反应有助于自然史
丙肝病毒感染。为了检验这一假设,我们将实现以下具体目标:1)HCV 是否会诱发
miR181水平不同,导致男性和女性HCV感染者或HCV-感染者产生不同的T细胞反应
解决患者? 2)男性和女性的CD4和CD8 T细胞中miR181的表达是否有差异?
女性健康受试者对 TCR 抗体(抗 CD3/CD28)或 HCV 抗原的刺激有何反应? 3)
通过功能获得或丧失检测,HCV 介导的 miR181 对宿主免疫反应的作用是什么?
包括病毒特异性 T 细胞反应?本补充提案的总体目标是采用
翻译方法以获得关于HCV是否可能在T细胞中诱导不同水平的miR181的统一概述
来自男性和女性受试者的细胞,可能转化为不同水平的宿主 T 细胞反应,因此
导致 HCV 感染的不同结果。
项目成果
期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV.
- DOI:10.3389/fimmu.2021.601298
- 发表时间:2021
- 期刊:
- 影响因子:7.3
- 作者:Nguyen LNT;Nguyen LN;Zhao J;Schank M;Dang X;Cao D;Khanal S;Chand Thakuri BK;Lu Z;Zhang J;Li Z;Morrison ZD;Wu XY;El Gazzar M;Ning S;Wang L;Moorman JP;Yao ZQ
- 通讯作者:Yao ZQ
Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.
- DOI:10.1002/hep.32008
- 发表时间:2021-11
- 期刊:
- 影响因子:0
- 作者:Nguyen LN;Nguyen LNT;Zhao J;Schank M;Dang X;Cao D;Khanal S;Thakuri BKC;Zhang J;Lu Z;Wu XY;El Gazzar M;Ning S;Wang L;Moorman JP;Yao ZQ
- 通讯作者:Yao ZQ
A Matter of Life or Death: Productively Infected and Bystander CD4 T Cells in Early HIV Infection.
- DOI:10.3389/fimmu.2020.626431
- 发表时间:2020
- 期刊:
- 影响因子:7.3
- 作者:Cao D;Khanal S;Wang L;Li Z;Zhao J;Nguyen LN;Nguyen LNT;Dang X;Schank M;Thakuri BKC;Zhang J;Lu Z;Wu XY;Morrison ZD;El Gazzar M;Ning S;Moorman JP;Yao ZQ
- 通讯作者:Yao ZQ
LncRNA HOTAIRM1 promotes MDSC expansion and suppressive functions through the HOXA1-miR124 axis during HCV infection.
LNCRNA HOTAIRM1在HCV感染期间通过HOXA1-MIR124轴促进MDSC的扩展和抑制功能。
- DOI:10.1038/s41598-020-78786-1
- 发表时间:2020-12-16
- 期刊:
- 影响因子:4.6
- 作者:Thakuri BKC;Zhang J;Zhao J;Nguyen LN;Nguyen LNT;Khanal S;Cao D;Dang X;Schank M;Wu XY;Morrison ZD;Gazzar ME;Li Z;Jiang Y;Ning S;Wang L;Moorman JP;Yao ZQ
- 通讯作者:Yao ZQ
Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.
KML001在人T细胞中端粒损伤通过p53-PGC-1α途径诱导线粒体功能障碍。
- DOI:10.1038/s41419-020-03238-7
- 发表时间:2020-12-02
- 期刊:
- 影响因子:9
- 作者:Schank M;Zhao J;Wang L;Li Z;Cao D;Nguyen LN;Dang X;Khanal S;Nguyen LNT;Thakuri BKC;Ogbu SC;Lu Z;Zhang J;Wu XY;Morrison ZD;El Gazzar M;Ning S;Moorman JP;Yao ZQ
- 通讯作者:Yao ZQ
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{{ truncateString('Zhi Q. Yao', 18)}}的其他基金
Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
针对 HBV/HIV 双重感染的纳米颗粒递送的双特异性基因编辑药物
- 批准号:
10403587 - 财政年份:2021
- 资助金额:
$ 9.62万 - 项目类别:
HIV infection-induced mitochondrial dysfunction and premature T cell aging
HIV感染引起的线粒体功能障碍和T细胞过早衰老
- 批准号:
10203459 - 财政年份:2021
- 资助金额:
$ 9.62万 - 项目类别:
Mitochondrial Dysfunction in Aging CD4 T cells in HIV-immune Non-responders.
HIV 免疫无反应者中衰老 CD4 T 细胞的线粒体功能障碍。
- 批准号:
10845843 - 财政年份:2021
- 资助金额:
$ 9.62万 - 项目类别:
Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
针对 HBV/HIV 双重感染的纳米颗粒递送的双特异性基因编辑药物
- 批准号:
10161447 - 财政年份:2021
- 资助金额:
$ 9.62万 - 项目类别:
Telomere loss and T cell aging in HBV vaccine response in HCV-infected individual
HCV 感染者的 HBV 疫苗反应中的端粒丢失和 T 细胞老化
- 批准号:
10265317 - 财政年份:2019
- 资助金额:
$ 9.62万 - 项目类别:
Telomere loss and T cell aging in HBV vaccine response in HCV-infected individual
HCV 感染者的 HBV 疫苗反应中的端粒丢失和 T 细胞老化
- 批准号:
10455526 - 财政年份:2019
- 资助金额:
$ 9.62万 - 项目类别:
Premature T cell aging and vaccine failure in chronic viral infection
慢性病毒感染中 T 细胞过早衰老和疫苗失败
- 批准号:
9023117 - 财政年份:2016
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ShEEP 针对多用户高级生物安全流式细胞仪的提案
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9211532 - 财政年份:2016
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Telomere attrition and T cell aging in vaccine failure during HIV infection
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- 批准号:
10581156 - 财政年份:2016
- 资助金额:
$ 9.62万 - 项目类别:
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