Immunoprotective Properties of Tissue-resident Memory T Cells in Mice and Humans within Mucosal Sites

PROJECT SUMMARYThis is an emergency competitive revision to our existing R01 AI121129. As part of this parent R01 entitled,"Immunoprotective properties of tissue-resident memory T cells in mice and humans within mucosal sites", weperform longitudinal sampling of the genital skin and HSV-2 lesions for both viral load as well as cytokine levels.This approach was highlighted in our recent paper in the Journal of Clinical Investigation (Roychoudhury et al,2020, PMID 32125285), in which we show that T cell-derived proteins including interferon gamma and granzymeB surge concurrently with local viral load. We now propose to use this successful approach to a second infectiousdisease, SARS-CoV-2.The COVID-19 pandemic is an unprecedented event in modern human history, with morbidity and mortality ratesdangerously high in the elderly and those with medical comorbidities. Given the current pandemic status, themost urgent goal is to lower case fatality and hospitalization rates. Front line providers need reliable tests torapidly triage infected patients according to severity and effective therapies to treat them. There is reason forhope; the mean time between presentation and need for hospitalization is a week for SARS-CoV-2 infectedpatients, which allows a much longer window to intervene than for influenza infection; clinical trials are alreadyassessing various small molecular agents and neutralizing antibodies. Thus, the goals of this application are touse an existing prospective cohort to assess multiple potential biomarkers of progression to severe disease atinitial clinical presentation, identify immunologic variables associated with viral elimination over ensuing weeks,and model the optimal timing, dose and duration of therapeutic interventions to prevent respiratory failure. Wewill leverage the currently surging local epidemic in Seattle; an IRB-approved protocol which is already enrollinginfected outpatient participants; a wide network of referring providers; and our multi-disciplinary team ofclinicians, T-cell immunologists, and mathematical modelers, who have existing, complementary tools andexisting collaborations, to rapidly produce and analyze critical data. We will share our results openly and in realtime with the international scientific community to assist in managing this global emergency.