miRNA-mediated premature T cell aging in vaccine failure during viral infection

病毒感染期间疫苗失败时 miRNA 介导的 T 细胞过早衰老

• 批准号: 8967564
• 负责人: Zhi Q. Yao
• 金额: $ 36.5万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967564
• 关键词: 5' -exoribonuclease; Accounting; Affect; Age; Aging; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Aging; Cell physiology; Chronic; Chronic Hepatitis C; Coculture Techniques; Elderly; Epigenetic Process; Exhibits; Failure; Functional disorder; Genes; Goals; HIV; HIV Infections; Health; Hemodialysis; Hepatitis B Vaccination; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Immune; Immune response; Immunization; Immunocompromised Host; Impairment; Individual; Infection; Interleukin-10; Interleukin-2; Killer Cells; Lectin; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Morbidity - disease rate; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Population; Public Health; Receptor Activation; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Risk Factors; Role; Signal Transduction; Signaling Molecule; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Translations; Transplantation; Up-Regulation; Vaccination; Vaccines; Virus; Virus Diseases; Work; aged; base; cancer transplantation; cell age; clinically significant; co-infection; cohort; exhaustion; improved; member; mortality; overexpression; premature; prevent; receptor; reconstitution; response; senescence; seroconversion; translational study; vaccine efficacy; vaccine response

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the mechanisms by which chronic infection mediates premature T cell aging through regulation of microRNAs and leading to blunted vaccine responses, with an aim to develop effective approaches to improve vaccine efficacy in virus-infected individuals. To this end, we will use a model of hepatitis B virus (HBV) vaccine failure in the setting of chronic hepatitis C virus (HCV) infection. The proposal is based on the fact that co-infection of HBV with HCV and/or HIV is common due to shared risk factors, and as such HBV vaccine is required to prevent super-infection and its associated increase in morbidity and mortality; however, vaccine responses in virus-infected individuals are often blunted. This phenomenon is also observed in the elderly, who frequently fail to respond to vaccinations and attempts to improve the rate of immunizations in both infected and aged populations have been unsuccessful. This is in part due to our poor understanding of the mechanisms that inhibit vaccine responses in these settings. 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. Remarkably, these alterations are associated with impaired CD4 T cell functions in HCV-infected individuals and are more prominent in HBV vaccine non- responders (HBV-NR) compared to age-matched HBV vaccine responders (HBV-R). 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 and vaccine responses during HCV infection remain unknown. In this proposal, we hypothesize that HCV-induced loss of miR181 mediates premature T cell aging by up-regulating KLRG1 and/or DUSP6 expressions, such that targeting these inhibitory pathways may rescue impaired CD4 T cell functions and subsequently boost blunted vaccine responses in virus-infected individuals. To test this hypothesis, we will carry out the following three specific aims: Aim 1 will define the epigenetic, transcriptional and translational mechanisms that control miR181 expression in T cells during HCV infection; Aim 2 will determine the role of miR181 in regulating KLRG1 and/or DUSP6 expression in T cells during HCV infection; Aim 3 will examine the consequences of miR181 loss and KLRG1/DUSP6 expression in T cell function and vaccine response in virus-infected individuals. This translational study is significant in that it provides a working model t explore mechanisms that may be fundamental to diminished vaccine responses in general, particularly in the setting of immunocompromise by HIV, hemodialysis, transplantation, and cancer.

描述（由申请人提供）：本提案的总体目标是阐明慢性感染通过调节 microRNA 介导 T 细胞过早衰老并导致疫苗反应减弱的机制，旨在开发有效的方法来提高疫苗功效病毒感染者。为此，我们将在慢性丙型肝炎病毒（HCV）感染的情况下使用乙型肝炎病毒（HBV）疫苗失败的模型。该提案基于以下事实：由于共同的危险因素，乙肝病毒与丙肝病毒和/或艾滋病毒合并感染很常见，因此需要乙肝疫苗来预防重复感染及其相关的发病率和死亡率增加；然而，病毒感染者的疫苗反应往往会减弱。这种现象在老年人中也存在，他们经常对疫苗接种没有反应，提高感染者和老年人群免疫接种率的尝试均未成功。部分原因是我们对这些环境中抑制疫苗反应的机制了解甚少。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 感染通过上调衰老标志物介导 T 细胞功能障碍，包括杀伤细胞凝集素样受体亚家族 G 成员 1 (KLRG1)和双特异性磷酸酶 6 (DUSP6)，伴随着 CD4 T 细胞中 microRNA-181a (miR181) 水平的下降。值得注意的是，这些改变与 HCV 感染者的 CD4 T 细胞功能受损有关，并且与年龄匹配的 HBV 疫苗应答者 (HBV-R) 相比，在 HBV 疫苗无应答者 (HBV-NR) 中更为突出。随着年龄的增长，KLRG1 上调并导致 T 细胞受体 (TCR) 信号传导受到抑制，而 DUSP6 则增加并导致 TCR 激活阈值重新校准； miR181 拒绝翻译一组与 T 细胞抑制相关的基因。然而，HCV 感染期间 miR181/KLRG1/DUSP6 表达以及 T 细胞过早衰老和疫苗反应调节的机制仍不清楚。在本提议中，我们假设 HCV 诱导的 miR181 缺失通过上调 KLRG1 和/或 DUSP6 表达来介导 T 细胞过早衰老，因此针对这些抑制途径可能会挽救受损的 CD4 T 细胞功能，并随后增强病毒中减弱的疫苗反应- 感染者。为了检验这一假设，我们将实现以下三个具体目标： 目标 1 将定义 HCV 感染期间控制 T 细胞中 miR181 表达的表观遗传、转录和翻译机制；目标2将确定HCV感染期间miR181在调节T细胞中KLRG1和/或DUSP6表达中的作用；目标 3 将检查 miR181 丢失和 KLRG1/DUSP6 表达对病毒感染个体 T 细胞功能和疫苗反应的影响。这项转化研究具有重要意义，因为它提供了一个工作模型来探索可能对总体疫苗反应减弱至关重要的机制，特别是在艾滋病毒、血液透析、移植和癌症导致免疫功能低下的情况下。