The impact of aging and thymus regeneration on tissue-resident CD8 T cell responses to viral lung infection and vaccination

衰老和胸腺再生对组织驻留 CD8 T 细胞对病毒肺部感染和疫苗接种反应的影响

• 批准号: 10626149
• 负责人: Ann Venables Griffith
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626149
• 关键词: 2019-nCoV; Acute; Affect; Age; Age Years; Aging; Animals; Antigens; Atrophic; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 severity; Cell Maturation; Cessation of life; Clinical Trials; Communicable Diseases; Complementary DNA; Coronavirus; Data; Elderly; Epitopes; Excision; Functional disorder; Generations; Human; Immunization; Immunize; Immunocompetence; Immunodominant Epitopes; Infection; Influenza; Interferons; Lung; Lung infections; Measures; Mediating; Middle East Respiratory Syndrome; Modeling; Modified Vaccinia Virus Ankara; Morbidity - disease rate; Mus; Natural regeneration; Patients; Peptides; Phenotype; Population; Production; Pulmonary Fibrosis; Pulmonary Inflammation; Role; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Site; Somatotropin; Specificity; Spleen; Stimulus; T cell response; T-Lymphocyte; Testing; Thymus Gland; Tissues; Vaccination; Vaccines; Viral; Viral Pathogenesis; Viral Pneumonia; Viral Vaccines; Virus; Virus Diseases; Vulnerable Populations; Weights and Measures; West Nile virus; Work; aged; clinically relevant; flu; improved; lung injury; mortality; novel coronavirus; older patient; pathogen; pathogenic virus; prevent; pulmonary vaccination; response; thymic regeneration; tissue resident memory T cell; vaccine efficacy; vaccine response

Summary The novel coronavirus, SARS-CoV-2, and the resulting Coronavirus Infectious Disease 2019 (COVID-19) has caused more than 500,000 deaths in the US. COVID-19 causes increased mortality and morbidity in patients over 65 years of age relative to younger patients. This is consistent with well-characterized age-associated decreases in responsiveness to viral infections such as SARS-1, MERS, and West Nile Virus. Likewise, responsiveness to vaccines for these viruses decline in the elderly. Therefore, approaches to enhance vaccine responsiveness in the elderly are critical to protect the most vulnerable population. A major contributor to the loss of immunocompetence with age is the atrophy of the thymus, the primary site of T cell maturation. Production of new naïve T cells depends on the availability of lymphopoietic niches within the thymic microenvironment. Since each T cell generally has one TCR specificity, the narrowing of the naïve T cell repertoire that results from thymic atrophy restricts the magnitude of the T cell response to new infections by reducing the number of naïve T cells capable of mounting a robust response against a given antigen. A well-known example is the loss of CD8 T cells recognizing an immunodominant influenza in the spleen and lungs during aging in mice. Likewise, recent work suggests loss of naïve T cells increases COVID-19 severity in elderly patients. Loss of naïve T cells specific for immunodominant epitopes may be exacerbated by dysfunction of the aged naïve T cells that do persist in older animals. For example, dysfunctional NP366-374-specific tissue-resident memory T cell (Trm) responses, which were suggested to arise as a result of thymus atrophy, were recently shown to promote persistent lung inflammation and exacerbate lung damage during viral pneumonia at 60 days post infection (d.p.i.) in aged mice. The thymus retains a remarkable capacity to regenerate, and regeneration increases the number of flu-specific T cells in aged spleen, however, it is not known whether thymic regeneration affects T cell responses in the lung, survival, or vaccine efficacy for flu, or other viral pathogens. Given the recently revealed role for Trm in age- associated viral pneumonia, and their potential role mediating vaccine responses, it is also important to understand whether thymic regeneration impacts the Trm population in aged lungs. We will evaluate the effect of thymus regeneration (mediated by Growth Hormone (GH) administration, an approach currently used in ongoing human clinical trials) on vaccine-mediated protection from viral pneumonia and secondary CD8 T cell responses using the well-characterized mouse-adapted flu model. As a second model, we have generated an experimental vaccine based on MVA (Modified Vaccinia Ankara) to be used for immunization ahead of infection with mouse- adapted SARS-CoV-2.

概括 新型冠状病毒 SARS-CoV-2 以及由此产生的 2019 年冠状病毒传染病 (COVID-19) 已经 在美国造成超过50万人死亡。 COVID-19 导致患者死亡率和发病率增加 相对于年轻患者，年龄超过 65 岁。这与明确的年龄相关特征是一致的 对 SARS-1、MERS 和西尼罗河病毒等病毒感染的反应性降低。同样地， 老年人对这些病毒疫苗的反应性下降。因此，加强疫苗接种的方法 老年人的反应能力对于保护最弱势群体至关重要。的主要贡献者 随着年龄的增长，免疫能力丧失是胸腺萎缩，而胸腺是 T 细胞成熟的主要部位。生产 新幼稚 T 细胞的产生取决于胸腺微环境中淋巴细胞生成生态位的可用性。 由于每个 T 细胞通常具有一种 TCR 特异性，因此幼稚 T 细胞库的缩小是由 胸腺萎缩通过减少初始感染的数量来限制 T 细胞对新感染的反应程度 T 细胞能够针对给定抗原产生强烈反应。一个众所周知的例子是 CD8 的丢失 在小鼠衰老过程中，T 细胞识别脾脏和肺部的免疫显性流感。同样，最近 研究表明，幼稚 T 细胞的丧失会增加老年患者的 COVID-19 严重程度。幼稚 T 细胞特异性丧失 免疫显性表位可能会因老化的初始 T 细胞的功能障碍而加剧，这些细胞确实持续存在 年长的动物。例如，功能失调的 NP366-374 特异性组织驻留记忆 T 细胞 (Trm) 反应， 被认为是由于胸腺萎缩而产生的，最近被证明可以促进持久性肺功能 在老年小鼠感染后 60 天 (d.p.i.) 期间，病毒性肺炎会导致炎症并加剧肺部损伤。 胸腺保留了显着的再生能力，再生会增加流感特异性的数量 衰老脾脏中的 T 细胞，然而，尚不清楚胸腺再生是否会影响肺中的 T 细胞反应， 流感或其他病毒病原体的存活率或疫苗功效。鉴于最近揭示的 Trm 在年龄方面的作用 相关的病毒性肺炎及其介导疫苗反应的潜在作用，也很重要 了解胸腺再生是否影响衰老肺部的 Trm 群体。我们将评估效果 胸腺再生（由生长激素 (GH) 介导，这是目前用于持续治疗的一种方法 人体临床试验）关于疫苗介导的病毒性肺炎保护和继发性 CD8 T 细胞反应 使用经过充分表征的小鼠适应流感模型。作为第二个模型，我们生成了一个实验 基于 MVA（改良安卡拉牛痘）的疫苗，用于在小鼠感染之前进行免疫接种 适应了 SARS-CoV-2。