Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects

PROJECT SUMMARYCoronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has already resulted in nearly 3million laboratory diagnosed infections and over 200,000 deaths worldwide. There is no known pre-existingimmunity to SARS-CoV-2 in humans or licensed therapeutics to combat or limit infection. In the absence ofthese pharmacological interventions, governments around the world have implemented stringent measures tothat curb the spread of SARS-CoV-2 to populations at risk of serious complications from infection. Efforts toidentify efficacious therapies and develop vaccines to counter infection and disease require time and ultimatelyneed to be guided by deep knowledge about this novel pathogen. Immune-directed therapies in particularrequire a detailed understanding of the immune responses generated not only in severe COVID-19 disease butalso in the vast majority of individuals who develop non-severe disease. Innate immunity serves as the frontlineresponse to counter the early stages of infection and but is also critical for regulating the ensuing adaptiveimmune response. In humans, anti-SARS-CoV-2 humoral immunity has gained significant attention while rolesfor innate immunity and memory T cell responses have not been extensively studied. However, knowledgegained from SARS-CoV-1 studies indicate that T cell immunity is critical in virus control. In these SARS-CoV-1infected mice, the induction of the innate type I Interferon signaling cascade is delayed. Yet mice lacking thisinnate immune response exhibited greater numbers of virus specific T cells in their lungs. Thus, thisdysregulated innate immune response impairs anti-SARS-CoV-1 T cell memory. Whether SARS-CoV-2infection induces protective memory T cells and if the durability of anti-SARS-CoV-2 T cell memory isinfluenced by innate immunity are all currently unexplored. In humans, the innate immune response induced innon-severe COVID-19 disease is not well characterized. However, preliminary studies in cultured cells andanimal models indicate that upon SARS-CoV-2 infection, there is a restricted and delayed induction of innateimmunity resulting in limited induction of cytokines and chemokines critical for immune cell recruitment. Wepredict that the vast majority of COVID-19 infected individuals will exhibit a dysregulated innate immuneresponse typified by delayed and limited inflammatory signaling. If true, such a compromised innate immuneresponse could in turn induce limited short-lived adaptive immunity. Indeed, studies from SARS-CoV-1infections indicate that humoral responses are short-lived in recovered patients. To our knowledge, no studieshave examined memory durability in COVID-19 subjects. In this proposal, we will interrogate samples from aprospective longitudinal cohort of Seattle residents to examine if aberrant T cell memory is induced duringSARS-CoV-2 infection and importantly if this impaired memory stems from dysregulated innate immunity.Furthermore, mechanistic studies in the hACE2 transgenic mouse model, where SARS-CoV-2 infection resultsin mild disease, will identify how innate immunity shapes anti-SARS CoV-2 T cell responses.