COVID-19 competitive revision: BALANCING PROTECTIVE IMMUNITY AND CHRONIC SEQUELAE BY RESIDENT CD8 T CELLS

Summary/AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an international outbreak of respiratory illness termed COVID-19. The primary determinant of outcome in COVID-19 infection is age, with the vast majority of morbidity and mortality occurring in the elderly. Current and emerging data suggests that survivors of severe COVID-19 infection will likely develop pulmonary fibrosis and persistent impairment of lung function. Given the potential catastrophic spreading of SARS-CoV-2 infection, it is predicted here that there will be a large number of individuals that recover from severe COVID-19 infection and develop permanent impairment in lung function due to lung fibrosis. However, there are no preventive means nor therapeutic interventions available to slow down and/or reverse lung fibrosis development following any viral pneumonia. We hypothesize that aged survivors of severe COVID-19 infection will develop persistent impairment of lung function due to pulmonary fibrosis even after complete resolution of acute infection. Furthermore, we hypothesize that recovered patients will pulmonary fibrosis will exhibit enhanced CD8 TRM cell presence in their respiratory tract and/or enhanced CD38 expression on CD8 TRM cells, contributing to tissue fibrosis and impaired lung function. To test these hypotheses, we have proposed two specific Aims in this study. Specific Aim 1: To determine respiratory CD8 TRM cell levels and quantitative lung fibrosis scores following severe SARS-CoV2 infection. Aim 2: To determine whether targeting CD8 TRM cells and/or CD38 pathway will attenuate post-viral pulmonary fibrosis and preserve lung function in elderly survivors of severe viral pneumonia. If successful, we expect that this study will establish an important role for CD8 TRM cells in lung fibrosis following COVID-19 pneumonia. Furthermore, this study will generate the necessary pre-clinical data to design early phase clinical trials using a new CD38 Ab that specific blocks CD38 ectoenzyme function as a novel therapy for recovered COVID-19 patients with lung fibrosis.