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

SARS-CoV-2的全球大流行呈现出高传染性和高传染性的不幸组合 导致自1917-1918年流感以来未曾见过的世界性后果的病态RNA病毒病原体 大流行。这突显了对预防或减轻疾病的疫苗的迫切需要。了解 SARS-CoV-2的自然宿主免疫反应关系到临床结果，是我们当前的中心议题 当我们开始为很可能的、不太理想的首轮谈判做准备时，需要有这样的视角 疫苗。了解在此之前和参与确定这一点的宿主免疫反应特征 临床结果的异质性需要指导我们开发改进的第二轮疫苗。T细胞 淋巴细胞减少可能是导致严重新冠肺炎发病的因素之一。当然，T细胞和B细胞 细胞免疫是对大多数病毒成功的长期反应所必需的。此外，我们和其他人 描述了患有和不患有糖尿病的老年人宿主T细胞免疫功能改变的一些特征 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 疯狂的免疫调节。我们将检验这一假设：在老年人中，较高水平的IL-6和 STNFR2和较低的幼稚T细胞频率排除了最初对新冠肺炎的适当T细胞反应 感染，也与以前的流感疫苗抗体水平较低有关。衰老和 耗竭的T细胞和Treg功能障碍损害对SARS-CoV-2和Tregs的Th1记忆反应的发展 预测病态的新冠肺炎结果。我们将确定较大的年龄、IL-6、sTNFR2或较低的幼稚 新冠肺炎暴露前CD4T细胞数量/功能与宿主T和B细胞应答相关 对于先前的流感疫苗和/或损害有效宿主Th1细胞对SARS的反应的发展- CoV-2和临床新冠肺炎预后的严重程度；并确定年龄较大和筋疲力尽， 新冠肺炎暴露前后出现的衰老或异常的Treg细胞表型与之相关 具有较低的SARS-CoV-2 Th1记忆应答和/或宿主T细胞和抗体应答 流感疫苗。

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.