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

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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.