A striking feature of Covid-19 is that the many overall features of the immune system’s response to SARS-CoV-2 are anomalous, inappropriate, and either excessive or inadequate. Many aspects of its viral pathogenesis, natural history, and host response-associated morbidity and mortality are not completely understood. Given this, there is an urgent need to better understand SARS-CoV-2 and Covid-19 immunobiology for potential countermeasures.
The objectives of this proposal are to identify the cellular immune responses to SARS-CoV-2 infection and to evaluate the immune-mediated pathology and host factors that might predispose patients to severe infection. There are two aims. Aim 1: To identify immune cell subsets and their potential developmental trajectories and interactions involved in advanced Covid-19 infection. We will take advantage of two complementary approaches to achieve this goal: high dimensional flow cytometry (1a) and RNA sequencing (1b). We will test the hypothesis that critical cellular elements driving the immune response to SARS-CoV-2 infection are associated with the severity and character of the ensuing Covid-19 clinical phenotype. The goal is to uncover the specific subsets of adaptive and innate immune cells involved in different clinical stages of the disease and delineate their developmental and functional statuses. Aim 2: To uncover the functions of T cells during Covid-19. SARS-CoV-2 infection promotes exhaustion of T cells as supported by recent data showing upregulation of exhaustion markers on cells of infected patients. Unfortunately, the function of these cells and the consequences of the exhaustion markers in the context of Covid-19 infection is unknown. In this aim we will test the hypothesis that the ability of the exhausted T cells to eliminate viral infected cells is abrogated due to inhibitory signals provided by these receptors. The goal of these studies is to uncover the mechanism of cellular killing during Covid-19 infection and test the premise that reinvigoration of exhausted T cells during early stages of the disease course could improve the ability of CD8+ T cells to eliminate infected cells.
