COVID-19: Role of naïve T cells, Age associated T cell senescence, and Dysfunctional Immune regulation in host response to SARS-CoV-2

COVID-19：幼稚 T 细胞、年龄相关 T 细胞衰老和免疫调节功能失调在宿主对 SARS-CoV-2 反应中的作用

• 批准号: 10152273
• 负责人: Donald D Anthony
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152273
• 关键词: 2019-nCoV; Age; Antibodies; Antibody Response; Antigens; Automobile Driving; B-Lymphocytes; Benign; Biological Assay; CD4 Positive T Lymphocytes; COVID-19; COVID-19 morbidity; COVID-19 pandemic; COVID-19 severity; COVID-19 vaccine; Cell Aging; Cell Count; Cells; Clinical; Cryopreservation; Defect; Development; Disease; Disease Outbreaks; Effectiveness; Elderly; Enrollment; Enzyme-Linked Immunosorbent Assay; FOXP3 gene; Flow Cytometry; Frequencies; Functional disorder; Funding; Goals; Heterogeneity; Human; Hypertension; IL2RA gene; Immune; Immune response; Immunity; Impairment; Individual; Infection; Inflammation Mediators; Inflammatory; Influenza; Interleukin-6; Knowledge; Lymphopenia; Medical center; Memory; Morbidity - disease rate; Outcome; Output; Participant; Peptides; Phenotype; Plasma; Play; Protocols documentation; RNA Viruses; Regulatory T-Lymphocyte; Role; SARS-CoV-2 exposure; SARS-CoV-2 infection; Sample Size; Sampling; Severe Acute Respiratory Syndrome; Site; T cell response; T memory cell; T-Lymphocyte; TNF gene; Th1 Cells; Thymus Gland; Time; Vaccine Design; Vaccines; Virus; Virus Diseases; aged; cell age; cohort; comorbidity; coronavirus disease; enzyme linked immunospot assay; exhaust; experience; immunogenicity; immunological status; immunoregulation; immunosenescence; improved; inflammatory marker; influenza virus vaccine; mortality; pandemic disease; pandemic influenza; pathogenic virus; patient oriented; patient population; prevent; prospective; research study; respiratory; response; senescence; severe COVID-19

The global pandemic of SARS-CoV-2 presents the unfortunate combination of a highly contagious and highly morbid RNA virus pathogen that is responsible for a world-wide outcome not seen since the 1917-1918 flu pandemic. This highlights the urgent need for a vaccine that prevents or mitigates disease. Understanding the natural host immune response to SARS-CoV-2 as it relates to clinical outcome is at the center of our current needed perspective as we embark on preparing for the very likely, less than ideal effectiveness on initial round vaccine. Understanding host immune response features that precede and participate in determining this heterogeneity in clinical outcome is needed to guide us forward to an improved second round vaccine. T cell lymphopenia may be one factor that correlates with severe COVID-19 morbidity. Certainly, both T cell and B cell immunity are required for a successful long term response to most all viruses. Additionally, we and others have described a number of features of host T cell immunity altered in older aged individuals with and without viral infection, including lymphopenia, naïve T cell numerical and functional defects, T cell senescence and deranged immune regulation. We will examine the hypothesis that: In the elderly, higher levels of IL-6 and sTNFR2, and lower frequencies of naïve T cells preclude initial adequate T cell responses to COVID-19 infection and are also associated with lower antibody levels to prior Influenza vaccine. Senescent and exhausted T cells and dysfunction in Tregs impair development of Th1 memory responses to SARS-CoV-2 and predict morbid COVID-19 outcome. We will Determine whether older age, IL-6, sTNFR2, or lower naïve CD4 T cell number/function prior to COVID-19 exposure is associated with host T and B cell response to prior influenza vaccine and/or impaired development of effective host Th1 cell response to SARS- Cov-2 and severity of clinical COVID-19 outcomes; and Determine whether older age and exhausted, senescent or aberrant Treg cell phenotype present before or after COVID-19 exposure is associated with lower SARS-CoV-2 Th1 memory response and/or host T cell and antibody response to prior influenza vaccine.

SARS-CoV-2的全球大流行呈现出高传染性和高风险的不幸组合。 自1917-1918年流感以来从未见过的一种引起世界范围后果的病态RNA病毒病原体 流行病这突出表明迫切需要一种预防或减轻疾病的疫苗。了解 自然宿主对SARS-CoV-2的免疫反应与临床结果有关，这是我们目前研究的中心。 在我们着手为第一轮很可能不太理想的效果做准备时， 疫苗了解宿主免疫反应的特点，之前和参与决定这一点， 需要临床结果的异质性来指导我们改进第二轮疫苗。T细胞 淋巴细胞减少症可能是与严重COVID-19发病率相关的一个因素。当然，T细胞和B细胞 细胞免疫是对大多数病毒的成功的长期应答所必需的。此外，我们和其他 已经描述了宿主T细胞免疫在老年个体中改变的许多特征， 病毒感染，包括淋巴细胞减少症、幼稚T细胞数量和功能缺陷、T细胞衰老和 紊乱的免疫调节我们将检验以下假设：在老年人中，IL-6和 sTNFR 2和较低频率的幼稚T细胞阻碍了对COVID-19的初始充分T细胞应答 感染，也与先前流感疫苗的抗体水平较低有关。衰老和 耗尽的T细胞和T细胞功能障碍损害了对SARS-CoV-2的Th 1记忆反应的发展， 预测病态的COVID-19结果。我们将确定是否老年、IL-6、sTNFR 2或较低的初治 COVID-19暴露前的CD 4 T细胞数量/功能与宿主T和B细胞应答相关 先前的流感疫苗和/或对SARS的有效宿主Th 1细胞应答的发展受损- COV-2和临床COVID-19结果的严重程度;并确定是否年龄较大和疲惫， COVID-19暴露前后存在的衰老或异常Treg细胞表型与 较低的SARS-CoV-2 Th 1记忆应答和/或宿主T细胞和抗体应答， 流感疫苗。