Mechanism of telomere attrition and premature T cell aging during HCV infection

HCV感染过程中端粒磨损和T细胞过早衰老的机制

基本信息

批准号：
10745519
负责人：
Juan Zhao
金额：
$ 27.63万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745519
关键词：
Acceleration Accounting Administrative Supplement Affect Aftercare Aging Antiviral Agents Apoptosis Apoptotic Award Biological Models Biomedical Research CD4 Positive T Lymphocytes Cell Aging Cell Nucleus Cell Separation Cell physiology Chronic Chronic Hepatitis C Communicable Diseases Competence DNA DNA Damage DNA Repair DNA biosynthesis Development Disease Down-Regulation Environment Enzymes Exhibits Functional disorder Genome Stability Genomic Instability Goals HIV Health Heat-Shock Proteins 90 Hepatitis C Hepatitis C virus Human Immune Immune System Diseases Immune response Immunity Immunocompetence Impairment Individual Infection Inflammatory Institution Mediating MicroRNAs Modeling Molecular Nuclear Import Nuclear Pore Complex Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Process Proteins RNA-Directed DNA Polymerase Research Research Personnel Research Training Role Scientist Signal Transduction T cell response T-Lymphocyte TERF2 gene TP53 gene Telomerase Telomere Maintenance Telomere Shortening Testing Training Ubiquitin Viral Virus Diseases age related ataxia telangiectasia mutated protein career development clinically significant design disadvantaged women exhaustion functional disability functional improvement improved next generation novel nuclease premature prevent receptor recruit senescence student training success telomere translational approach translational study vaccine access virus host interaction

项目摘要

Chronic viral infections appear to drive premature T cell aging, as evidenced by accelerated shortening of telomeres. However, how telomeres are trimmed to drive T cell aging during viral infection remains unclear. The goal of this study is to elucidate the mechanisms by which chronic viral infection accelerates the telomere attrition that may cause premature T cell aging, so as to develop effective means to improve cellular functions in virally infected individuals. To this end, we will employ hepatitis C virus (HCV) infection as a model system because i) HCV has a high rate (70%-80%) of persistence in humans; ii) the recent success in developing direct-acting antivirals (DAA) has resulted in a high rate (>95%) of viral clearance, providing an excellent opportunity to study the role of viral infection in modulating the host immunity before and after treatment in humans; iii) there is no vaccine available for HCV thus far, in part due to the unclear virus-host interactions that induce T cell senescence and immune dysfunction; and iv) we have recently found that CD4 T cells derived from HCV patients exhibit enhanced DNA damage and telomere erosion that are associated with a profound apoptotic and aging phenotype. Mechanistically, we have recently demonstrated that telomeric DNA damage and repair machineries are impaired in CD4 T cells during HCV infection: while the human telomerase reverse transcriptase (hTERT, the catalytic unit of telomerase that prolongs telomeric DNA) remains intact; the telomeric repeat binding factor 2 (TRF2, a telomere shelterin protein that protects telomeres from DNA damage) and the ataxia-telangiectasia mutated (ATM, a kinase that repairs the DNA damage) are inhibited in HCV CD4 T cells. We thus hypothesize that either an increased nuclease-mediated telomere trimming by aberrant telomeric DNA damage and repair signaling and/or a compromised telomeric DNA elongation is involved in the telomere attrition during chronic HCV infection. We designed two specific aims and will employ a translational approach using CD4 T cells from HCV-infected subjects before and after DAA treatment, to test our hypothesis. In Aim 1, we will identify the role of TRF2 in the telomeric DNA damage and telomere attrition during HCV infection. In Aim 2, we will elucidate the mechanisms involved in compromising telomeric DNA elongation during HCV infection. This translational study is novel and clinically significant in that it will explore mechanisms fundamental to diminishing T cell responses, and will address important questions as to how telomeric DNA is damaged to accelerate T cell aging and whether interfering with the enzyme involved in disrupting telomere integrity can remodel T cell function during viral infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of various chronic infectious diseases, including but not limited to HCV infection.

慢性病毒感染似乎会导致 T 细胞过早衰老，这一点可以通过加速缩短 T 细胞来证明。端粒。然而，病毒感染期间端粒如何被修剪以驱动 T 细胞老化仍不清楚。这这项研究的目的是阐明慢性病毒感染加速端粒磨损的机制可能会导致T细胞过早衰老，从而开发有效的手段来改善病毒性细胞功能感染者。为此，我们将采用丙型肝炎病毒 (HCV) 感染作为模型系统，因为 i) HCV在人类中的持续率很高（70%-80%）； ii) 最近在开发直接作用方面取得的成功抗病毒药物 (DAA) 实现了高病毒清除率 (>95%)，提供了绝佳的研究机会病毒感染在人类治疗前后调节宿主免疫力的作用； iii) 没有迄今为止，还没有针对 HCV 的疫苗，部分原因是导致 T 细胞衰老的病毒与宿主相互作用尚不明确和免疫功能障碍； iv) 我们最近发现来自 HCV 患者的 CD4 T 细胞表现出与严重细胞凋亡和衰老相关的 DNA 损伤和端粒侵蚀增强表型。从机制上讲，我们最近证明端粒 DNA 损伤和修复机制 HCV 感染期间 CD4 T 细胞受损：而人端粒酶逆转录酶 (hTERT、延长端粒 DNA 的端粒酶催化单元保持完整；端粒重复结合因子 2（TRF2，一种端粒庇护蛋白，可保护端粒免受 DNA 损伤）和共济失调毛细血管扩张突变（ATM，一种修复 DNA 损伤的激酶）在 HCV CD4 T 细胞中受到抑制。因此我们假设异常端粒 DNA 损伤和修复导致核酸酶介导的端粒修剪增加信号传导和/或端粒 DNA 延伸受损与慢性应激过程中的端粒磨损有关。丙肝病毒感染。我们设计了两个具体目标，并将采用一种使用 CD4 T 细胞的转化方法 DAA 治疗前后的 HCV 感染受试者，以检验我们的假设。在目标 1 中，我们将确定角色 TRF2 在 HCV 感染期间端粒 DNA 损伤和端粒磨损中的作用。在目标 2 中，我们将阐明 HCV 感染期间端粒 DNA 延长受损的机制。这个翻译该研究具有新颖性和临床意义，因为它将探索减少 T 细胞的基本机制反应，并将解决端粒 DNA 如何被破坏以加速 T 细胞衰老的重要问题干扰参与破坏端粒完整性的酶是否可以重塑 T 细胞功能病毒感染期间。了解这些机制对于开发改善免疫的方法至关重要各种慢性传染病（包括但不限于丙型肝炎病毒感染）的反应。