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.

总结 新型冠状病毒SARS-CoV-2和由此产生的2019冠状病毒传染病（COVID-19） 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 65岁以上的患者相对于年轻患者。这与特征良好的年龄相关性 降低对病毒感染如SARS-1、MERS和西尼罗河病毒的反应性。同样地， 老年人对这些病毒疫苗的反应性下降。因此，增强疫苗的方法 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，免疫活性的丧失是胸腺的萎缩，胸腺是T细胞成熟的主要部位。生产 新的幼稚T细胞的产生取决于胸腺微环境中淋巴细胞生成小生境的可用性。 由于每个T细胞通常具有一种TCR特异性，因此由TCR特异性导致的幼稚T细胞库的缩小可能是一个很大的问题。 胸腺萎缩限制了T细胞对新感染的反应的大小， 能够对给定抗原产生强烈反应的T细胞。一个众所周知的例子是CD 8的丢失 小鼠衰老过程中脾和肺中识别免疫显性流感的T细胞。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 对于免疫显性表位，老年幼稚T细胞的功能障碍可能会加剧， 年长的动物例如，功能失调的NP 366 -374特异性组织驻留记忆T细胞（Trm）应答， 被认为是胸腺萎缩的结果，最近被证明可以促进持续的肺 在感染后60天（d.p.i.）老年小鼠 胸腺保留了非凡的再生能力，再生增加了流感特异性抗体的数量。 然而，胸腺再生是否影响肺中的T细胞反应尚不清楚， 存活率或疫苗对流感或其他病毒病原体的效力。考虑到最近揭示的Trm在年龄方面的作用- 相关病毒性肺炎及其介导疫苗应答的潜在作用， 了解胸腺再生是否影响老年肺中的Trm群体。我们将评估 胸腺再生（由生长激素（GH）给药介导，这是一种目前正在进行的 人类临床试验）对疫苗介导的病毒性肺炎和继发性CD 8 T细胞应答的保护作用 使用了一个很好的小鼠适应流感模型。作为第二个模型，我们已经生成了一个实验性的 基于MVA（改良的安卡拉牛痘）的疫苗，用于在感染小鼠之前进行免疫接种， 适应SARS-CoV-2。