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: 10527615
• 负责人: Ann Venables Griffith
• 金额: $ 23.25万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527615
• 关键词: 2019-nCoV; Acute; Affect; Age; Age-Years; Aging; Animals; Antigens; Atrophic; CD8-Positive T-Lymphocytes; 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; Severities; Site; Somatotropin; Specificity; Spleen; Stimulus; T cell response; T memory cell; 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; base; clinically relevant; flu; human old age (65+); improved; lung injury; mortality; novel coronavirus; older patient; pathogen; pathogenic virus; prevent; pulmonary vaccination; response; thymic regeneration; 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和由此产生的冠状病毒感染疾病2019（Covid-19）具有 在美国造成500,000多人死亡。 COVID-19导致患者的死亡率和发病率提高 相对于年轻患者，超过65岁以上。这与特征良好的年龄相关 对病毒感染的反应性降低，例如SARS-1，MERS和西尼罗河病毒。同样地， 这些病毒对疫苗的反应能力在古老的​​情况下下降。因此，增强疫苗的方法 古老的响应能力对于保护最脆弱的人群至关重要。一个主要贡献者 与年龄的免疫能力丧失是胸腺的萎缩，这是T细胞成熟的主要部位。生产 新的幼稚T细胞取决于胸膜微环境内淋巴生物壁球的可用性。 由于每个T细胞通常都有一个TCR特异性，因此幼稚的T细胞库的狭窄 胸腺萎缩通过减少幼稚的​​数量来限制T细胞对新感染的T细胞反应的大小 T细胞能够安装针对给定抗原的鲁棒反应。一个众所周知的例子是CD8的损失 T细胞在小鼠衰老过程中识别出脾脏和肺部的免疫主导影响力。同样，最近 工作表明，幼稚的T细胞的损失会增加老年患者的共同严重程度。特异性幼稚T细胞的丧失 对于免疫主导的表位可能会因持续存在的老年幼稚T细胞功能障碍而加剧 年龄较大的动物。例如，功能失调的NP366-374特异性组织记忆T细胞（TRM）响应 被认为是由于胸腺萎缩而引起的，最近被证明可以促进持续性肺 年龄小鼠感染后60天（D.P.I.），病毒性肺炎期间的炎症和加剧的肺损伤。 胸腺保留了显着的再生能力，再生增加了流感特异性的数量 然而，老年脾脏中的T细胞尚不清楚胸腺再生是否影响肺中的T细胞反应， 流感或其他病毒病原体的生存或疫苗效率。鉴于最近揭示了TRM在年龄中的作用 - 相关的病毒性肺炎及其介导疫苗反应的潜在作用，对于 了解胸腺再生是否影响老年肺的TRM人群。我们将评估 胸腺再生（由生长激素（GH）给药介导，一种目前正在进行的方法 人类临床试验）关于疫苗介导的免受病毒肺炎和次级CD8 T细胞反应的保护 使用良好的小鼠适应性流感模型。作为第二个模型，我们已经生成了一个实验 基于MVA（修饰的vacinia ankara）的疫苗，用于在感染小鼠之前进行免疫接种 改编的SARS-COV-2。