Impact of Immunotherapy on Viral Immunity in Humans

COVID-19 disease (caused by SARS-CoV-2) typically manifests as a period of low-grade illness followed byprogression in some to an acute phase illness after 7-10 days characterized by pneumonia, and progression toARDS, cytokine release syndrome, and multiorgan failure at 10-14 days. This progression is thought to reflectsome 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 anoveraggressive immune response. In the case of COVID-19 disease it is unclear which side of the diseasepathology spectrum predominates and whether this differs in patients with mild versus severe disease or overthe course of disease in an individual patient. In general, we know little about the immune response to COVID-19 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 immunologicalmemory. There are major questions about the nature of the innate and adaptive immune response duringCOVID-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 addressthe following questions: Are these (and other) innate immune cells activated and do these activation stateschange with disease severity or over time? Do these innate immune cell responses link to the responses ofadaptive immune cells? Similarly, our expertise in adaptive immunity can be leveraged to address the followingquestions: How do CD4 T cell responses including Tfh and CD8 T cell responses relate to COVID-19 disease? CanB cell responses to the virus be detected? What happens to these cells in convalescence? Is immunologicalmemory established? Are the same B cell and T cell clonotypes responding in the acute phase and followingresolution? Are immune cells altered by the initial virus challenge, leading to aberrant responses in the secondweek when the virus re-emerges at a new site (alveoli, heart or other sites)? Which adaptive immune responsesprovide protection against the virus? Working with blood and tissue samples from COVID-19 cohorts at UPennand MGH, we will study T cell responses in relation to severity and stage of disease (including kinetics, activationand differentiation states, development into memory and repertoire), B cell and antibody dynamics andrepertoire at different stages of disease, monocyte populations and attendant cytokines as key determinants ofoutcome in COVID-19 disease. We will share de-identified datasets rapidly with the community (following initialquality assessment) via outward-facing portals.