Gender difference in miRNA-mediated T cell aging during viral infection

主要的种族和性别差异已被确认在丙型肝炎病毒（HCV）的自然史 感染;然而，对这种现象的潜在机制仍然知之甚少。对研究 由于HCV感染的自然史，人们已经充分认识到i）白色女性有8倍的机会 急性HCV感染的自发病毒清除; ii）具有基因型1HCV的非洲裔美国人（AA）男性 感染具有比白种美国人（CA）更高病毒持续性或慢性感染率;和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，但与以下因素有关： 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感染导致T细胞功能障碍， 调节衰老标志物，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），伴随着CD4 T细胞中microRNA-181 a（miR181）水平的下降。 这些观察结果表明，宿主在慢性感染期间不能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自然病程的影响 感染可能是由于病毒诱导的miRNA介导的信号传导的差异。事实上，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增加 并导致TCR激活阈值的重新校准; miR181下降以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 HCV感染时T细胞过早老化的调节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，有助于自然史， HCV感染。为了验证这一假设，我们将进行以下具体目标：1）HCV是否诱导 不同水平的miR181，导致男性和女性HCV感染者或HCV阴性者的不同T细胞应答。 解决患者？2)男性和女性的CD4和CD8 T细胞中miR181的表达是否存在差异？ 女性健康受试者对TCR抗体（抗CD3/CD28）或HCV抗原刺激的反应？第三章 HCV介导的miR181在宿主免疫应答中的作用是什么？ 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是否可以在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T细胞，这可能转化为不同水平的宿主T细胞应答，因此 导致HCV感染的不同结果。

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.