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: 10356083
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356083
• 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; 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; vaccine efficacy; vaccine immunogenicity

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一种高度传染性和高度传染性的不幸组合。 病态 RNA 病毒病原体，造成自 1917-1918 年流感以来从未见过的世界范围后果 这凸显了对预防或减轻疾病的疫苗的迫切需求。 对 SARS-CoV-2 的自然宿主免疫反应与临床结果相关，是我们当前研究的核心 当我们开始为第一轮中很可能出现的、不太理想的效果做准备时，我们需要有不同的视角 了解先于并参与确定该疫苗的宿主免疫反应特征。 临床结果的异质性需要指导我们改进第二轮 T 细胞疫苗。 淋巴细胞减少症可能是与严重的 COVID-19 发病相关的因素之一，当然，T 细胞和 B 细胞都是如此。 对大多数病毒的成功长期反应需要细胞免疫。 描述了老年人宿主 T 细胞免疫改变的许多特征，无论是否患有 病毒感染，包括淋巴细胞减少、幼稚 T 细胞数量和功能缺陷、T 细胞衰老和 我们将检验以下假设：在老年人中，IL-6 和 IL-6 水平较高。 sTNFR2 和较低频率的初始 T 细胞妨碍了 T 细胞对 COVID-19 的初始充分反应 感染，也与先前流感疫苗的抗体水平较低有关。 T 细胞耗尽和 Tregs 功能障碍会损害 Th1 对 SARS-CoV-2 的记忆反应的发展， 我们将确定是否年龄较大、IL-6、sTNFR2 或较低的初始水平。 暴露于 COVID-19 之前的 CD4 T 细胞数量/功能与宿主 T 和 B 细胞反应相关 先前的流感疫苗和/或宿主 Th1 细胞对 SARS 的有效反应受损 Cov-2 和 COVID-19 临床结果的严重程度；以及 确定年龄是否较大、是否精疲力尽、 在接触 COVID-19 之前或之后出现的衰老或异常 Treg 细胞表型与此相关 SARS-CoV-2 Th1 记忆反应和/或宿主 T 细胞和抗体对先前的反应较低 流感疫苗。

项目成果

Rheumatoid arthritis and older age are associated with lower humoral and cellular immune response to primary series COVID-19 mRNA vaccine.

类风湿性关节炎和老年与初级系列 COVID-19 mRNA 疫苗的体液和细胞免疫反应较低有关。

• DOI: 10.1016/j.vaccine.2023.08.033
• 发表时间: 2023
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Dudley,HollyM;O'Mara,Megan;Auma,Ann;Gong,Jenny;Ross,Yael;Gurevich,Natalie;Carbone,Sarah;Reihs,Alex;Nguyen,Ynez;McComsey,GraceA;Cao,Yi;Balazs,AlejandroB;Gordesky,Larraine;Payne,Michael;Singer,Nora;Kostadinova,Lenche;Wilso
• 通讯作者: Wilso

COVID-19 vaccination experience in patients with rheumatoid arthritis treated at a single VA medical center.

• DOI: 10.1016/j.jvacx.2023.100295
• 发表时间: 2023-08
• 期刊: VACCINE: X
• 影响因子: 3.8
• 作者: Doumeth, Sarah Abi;Gong, Jenny;Silversteyn, Laura;O'Mara, Megan;Singh, Shivali;Anthony, Donald;Mattar, Maya
• 通讯作者: Mattar, Maya

Dr. Kostadinova et al reply.

Kostadinova 博士等人回复。

• DOI: 10.3899/jrheum.2023-0485
• 发表时间: 2023
• 期刊: The Journal of rheumatology
• 作者: Kostadinova,Lenche;Lange,Alyssa;Damjanovska,Sofi;Gad,Ibtissam;Syed,Sameena;Siddiqui,Husna;Yousif,Patrick;Kowal,CorinneM;Shive,Carey;Burant,Christopher;Singer,Nora;Bej,Taissa;Al-Kindi,Sadeer;Wilson,Brigid;Mattar,Maya;Zidar,D
• 通讯作者: Zidar,D