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

• 批准号: 9896225
• 负责人: Zhi Q. Yao
• 金额: $ 9.62万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9896225
• 关键词: Acute Hepatitis C; Affect; African American; Age; Aging; Biological Assay; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Aging; Cell physiology; Cells; Characteristics; Chronic Hepatitis C; Disease; Exhibits; Fc Receptor; Female; Functional disorder; Gender; Genes; Genotype; Goals; Hepatitis C; Hepatitis C virus; Human; Immune response; Immunity; Impairment; Individual; Infection; Killer Cells; Lectin; Mediating; MicroRNAs; Modeling; Natural History; Outcome; Patients; Phosphoric Monoester Hydrolases; Play; Race; Receptor Activation; Receptor Signaling; Regulation; Role; Signal Transduction; T cell regulation; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Time; Translating; Translations; Up-Regulation; Variant; Viral; Viral Antigens; Viral Load result; Virus; Virus Diseases; base; caucasian American; chronic infection; gender difference; immunological status; improved; loss of function; male; member; premature; racial difference; receptor; response; translational approach

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.

在丙型肝炎病毒的自然历史中，主要的种族和性别差异已被认识到。 感染；然而，这一现象的潜在机制仍然知之甚少。在研究 丙型肝炎病毒感染的自然病史，人们已经很好地认识到：i)白人女性有8倍以上的机会 急性丙型肝炎病毒感染的自发病毒清除；ii)携带1型丙型肝炎病毒的非裔美国人(AA)男性 感染的病毒持久性或慢性感染率高于高加索美国人(CA)；以及iii)这些 差异不是由基线病毒载量、基因类型或疾病特征来解释的，而是与 宿主的免疫状态，特别是T细胞的反应。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，慢性丙型肝炎病毒感染导致T细胞功能障碍通过上调- 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DUAL 特异性磷酸酶6(DUSP6)，伴随着CD4T细胞中microRNA-181a(MiR181)水平的下降。 这些观察表明，宿主在慢性感染期间无法清除病毒可能是由于 MicroRNA介导的宿主免疫功能受损以及种族/性别对丙型肝炎病毒自然病史的影响 感染可能是由于病毒诱导的、miRNA介导的信号不同所致。事实上，随着年龄的增长， KLRG1上调并导致T细胞受体(TCR)信号的抑制，而DUSP6增加 并导致TCR激活阈值的重新校准；miR181拒绝允许一组基因的翻译 与T细胞抑制有关。然而，miR181/KLRG1/DUSP6表达的潜在机制和 丙型肝炎病毒感染者T细胞早衰的调节及其与性别差异的关系 丙型肝炎病毒感染的自然病史仍不清楚。因此，我们假设病毒诱导的microRNAs可能 表现出性别差异，这可能会影响T细胞反应，这对自然病程有贡献 丙型肝炎病毒感染。为了验证这一假设，我们将实现以下具体目标：1)丙型肝炎病毒是否会诱导 不同水平的miR181，导致男性和女性感染丙型肝炎病毒或丙型肝炎病毒的T细胞反应不同。 已解决的患者？2)男性和女性在CD4和CD8T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)或丙型肝炎病毒抗原刺激的反应？3 通过功能增减分析，丙型肝炎病毒介导的miR181在宿主免疫反应中的作用是什么？ 包括病毒特异性T细胞反应？这个补充提案的总体目标是采用一个 获得关于丙型肝炎病毒是否可能在T细胞中诱导不同水平的miR181的统一概述的翻译方法 来自男性和女性受试者的细胞，这可能转化为不同水平的宿主T细胞反应，因此 导致丙型肝炎病毒感染的不同结果。

项目成果

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: Frontiers in immunology
• 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: Hepatology (Baltimore, Md.)
• 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: Frontiers in immunology
• 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: Scientific reports
• 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: Cell death & disease
• 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