Core D: Antigen Receptor Identification and Tracking Core

COVID-19 disease (caused by SARS-CoV-2) typically manifests as a period of low-grade illness followed by progression in some to an acute phase illness after 7-10 days characterized by pneumonia, and progression to ARDS, cytokine release syndrome, and multiorgan failure at 10-14 days. This progression is thought to reflect some combination of increasing viral load, cytopathic effects, translocation into lower airways and other tissues. During acute respiratory viral infections, pathology and disease can result from either an insufficient or an overaggressive immune response. In the case of COVID-19 disease it is unclear which side of the disease pathology spectrum predominates and whether this differs in patients with mild versus severe disease or over the course of disease in an individual patient. In general, we know little about the immune response to COVID19 disease, which cell types contribute to control and mild disease and which are involved in severe disease. Moreover, in patients who successfully control disease and recover, we know nothing about immunological memory. There are major questions about the nature of the innate and adaptive immune response during COVID-19 disease that can be directly addressed by the unique infrastructure of our existing U19. For example, using our expertise on innate immune cells including myeloid cells, dendritic cells and MAIT cells, we can address the following questions: Are these (and other) innate immune cells activated and do these activation states change with disease severity or over time? Do these innate immune cell responses link to the responses of adaptive immune cells? Similarly, our expertise in adaptive immunity can be leveraged to address the following questions: How do CD4 T cell responses including Tfh and CD8 T cell responses relate to COVID-19 disease? Can B cell responses to the virus be detected? What happens to these cells in convalescence? Is immunological memory established? Are the same B cell and T cell clonotypes responding in the acute phase and following resolution? Are immune cells altered by the initial virus challenge, leading to aberrant responses in the second week when the virus re-emerges at a new site (alveoli, heart or other sites)? Which adaptive immune responses provide protection against the virus? Working with blood and tissue samples from COVID-19 cohorts at UPenn and MGH, we will study T cell responses in relation to severity and stage of disease (including kinetics, activation and differentiation states, development into memory and repertoire), B cell and antibody dynamics and repertoire at different stages of disease, monocyte populations and attendant cytokines as key determinants of outcome in COVID-19 disease. We will share de-identified datasets rapidly with the community (following initial quality assessment) via outward-facing portals