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) 这项建议的总体目标是阐明慢性病毒感染通过调节microRNA调节蛋白来调节T细胞过早老化和疫苗失效的机制，目的是开发有效的方法来提高病毒感染者的疫苗效力。为此，我们将使用一种乙肝病毒(HBVi)疫苗失败的模型设定慢性丙型肝炎病毒(HCV)感染。这项建议是基于这样一个事实，即由于共同的风险因素，乙肝病毒和丙型肝炎病毒混合感染是常见的，因此需要接种乙肝疫苗来防止重叠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通常是迟钝的。在经常对疫苗接种无效的老年人中也可以观察到这种现象；试图提高受感染人口和老年人口的免疫接种率的努力没有成功，部分原因是我们对在这些环境中抑制疫苗反应的机制缺乏了解。在研究慢性病毒感染对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，其机制是通过上调衰老标志物，包括杀伤细胞凝集素样受体亚家族G成员1(KLRG1)和双特异性磷酸酶6(DUSP6)，伴随着CD4T细胞microRNA-155(MiR155)水平的下降。值得注意的是，这些变化与丙型肝炎病毒感染者的CD4T细胞功能受损有关，与年龄匹配的乙肝疫苗应答者(HBVR)相比，这些变化在乙肝疫苗无应答者(HBVNR)中更为突出。已有研究表明，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；miR155的下降允许一组与T细胞抑制相关的靶基因的翻译。然而，在丙型肝炎病毒感染过程中miR155/KLRG1/DUSP6表达的潜在机制以及对T细胞过早老化和疫苗反应的调节仍不清楚。在这项提议中，我们假设丙型肝炎病毒诱导的miR155的丢失通过上调KLRG1和/或DUSP6的表达来调节T细胞的过早老化，从而靶向这些抑制通路可能拯救受损的CD4T细胞功能，并随后增强病毒感染个体的钝化疫苗应答。为了验证这一假设，我们将实现以下两个特定目标：目标1将定义控制miR155表达的转录和翻译机制，以及miR155在丙型肝炎病毒感染期间调节T细胞中KLRG1和/或DUSP6表达的作用；目标2将研究病毒感染个体中miR155丢失和KLRG1/DUSP6过表达对T细胞功能和疫苗反应的影响。这项转化性研究具有重要意义，因为它提供了一个工作模型，以探索可能是疫苗反应减弱的基本机制，特别是在艾滋病毒、血液透析、移植和癌症造成的免疫损害的背景下。