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

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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Zhi Q. Yao其他文献

Zhi Q. Yao的其他文献

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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:
Multiuser Advanced Confocal Microscope
多用户高级共焦显微镜
  • 批准号:
    9791445
  • 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:
    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
  • 资助金额:
    $ 9.62万
  • 项目类别:
ShEEP Proposal for a Multiuser Advanced Biosafe Flow Cytometer
ShEEP 针对多用户高级生物安全流式细胞仪的提案
  • 批准号:
    9211532
  • 财政年份:
    2016
  • 资助金额:
    $ 9.62万
  • 项目类别:
Telomere attrition and T cell aging in vaccine failure during HIV infection
HIV 感染期间疫苗失败时的端粒磨损和 T 细胞老化
  • 批准号:
    10581156
  • 财政年份:
    2016
  • 资助金额:
    $ 9.62万
  • 项目类别:

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