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
• 负责人: Zhi Q. Yao
• 金额: --
• 依托单位: JAMES H QUILLEN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023117
• 关键词: 5' -exoribonuclease; Accounting; Affect; Age; Aging; Antigens; B-Lymphocytes; Biological Markers; CD4 Positive T Lymphocytes; Cell Aging; Cell physiology; Cessation of life; Chronic; Chronic Hepatitis C; Coculture Techniques; Elderly; Epidemic; Exhibits; Failure; Functional disorder; Gene Targeting; 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; Mediating; MicroRNAs; Modeling; Morbidity - disease rate; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Population; Proteins; Receptor Activation; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Risk Factors; Role; Signal Transduction; Signaling Molecule; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Transforming Growth Factor beta; Translations; United States; Up-Regulation; Vaccination; Vaccines; Veterans; Virus; Virus Diseases; Work; aged; base; cancer transplantation; cell age; chronic liver disease; clinically significant; co-infection; cohort; cost; exhaustion; improved; member; mortality; overexpression; premature; prevent; public health relevance; 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 viral infection mediates premature T cell aging and vaccine failure through regulation of microRNA-regulated proteins, 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 i the setting of chronic hepatitis C virus (HCV) infection. The proposal is based on the fact that co-infection of HBV with HCV 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, in part due to our poor understanding of the mechanisms that inhibit vaccine responses in these settings. In studying the effect of chronic 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-155 (miR155) 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). It has been demonstrated that 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; and miR155 decline is known to permit translation of a set of target genes related to T cell inhibition. However, the mechanisms underlying miR155/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 miR155 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 two specific aims: Aim 1 will define the transcriptional and translational mechanisms that control miR155 expression and the role of miR155 in regulating KLRG1 and/or DUSP6 expression in T cells during HCV infection; Aim 2 will examine the consequences of miR155 loss and KLRG1/DUSP6 over-expression in T cell function and vaccine response in virus-infected individuals. This translational study is significant in that it provides a working model to 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） 该提案的总体目标是阐明慢性病毒感染通过调控 microRNA 调节蛋白介导 T 细胞过早衰老和疫苗失败的机制，旨在开发有效的方法来提高病毒感染个体的疫苗功效。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）疫苗失败模型。该建议基于以下事实：由于共同感染，乙型肝炎病毒与丙型肝炎病毒共同感染很常见。危险因素，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的增加；然而，病毒感染者的疫苗反应往往减弱，这种现象也经常出现在老年人身上。疫苗接种；以及提高感染者和老年人群免疫接种率的尝试均未成功，部分原因是我们在研究慢性病毒感染对 T 细胞的影响时对抑制疫苗反应的机制了解甚少。功能， 我们和其他人最近发现，慢性 HCV 感染通过衰老标志物的上调介导 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)，同时伴有CD4 T 细胞中 microRNA-155 (miR155) 水平的下降 值得注意的是，这些变化与 HCV 感染个体中 CD4 T 细胞功能受损有关。与年龄匹配的 HBV 疫苗应答者 (HBV-R) 相比，KLRG1 在 HBV 疫苗无应答者 (HBV-NR) 中显着。已证明，随着年龄的增长，KLRG1 上调并导致抑制 T 细胞受体 (TCR)。 ) ) 信号传导；而 DUSP6 增加并导致 TCR 激活阈值的重新校准；已知 miR155 下降可允许与 T 细胞抑制相关的一组靶基因的翻译。 HCV 感染期间 miR155/KLRG1/DUSP6 的表达以及对 T 细胞过早衰老和疫苗反应的调节仍然未知。在本提议中，我们认为 HCV 诱导的 miR155 缺失通过上调 KLRG1 和/或 DUSP6 表达来介导 T 细胞过早衰老。 ，这样一来，针对这些抑制途径可以挽救受损的 CD4 T 细胞功能，并随后增强病毒感染个体中减弱的疫苗反应。为了检验这一假设，我们将进行以下两个具体研究。目标：目标 1 将定义控制 miR155 表达的转录和翻译机制，以及 miR155 在 HCV 感染期间调节 T 细胞中 KLRG1 和/或 DUSP6 表达的作用；目标 2 将检查 miR155 缺失和 KLRG1/DUSP6 过度表达的后果。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至关重要的机制。总体而言，疫苗反应减弱，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。