Modulation of Lung Immune Responses to Viral Infection

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Modified Project Summary/Abstract Section Severe COVID-19 has been associated with long term pulmonary sequelae. Patients with severe COVID-19 develop acute respiratory distress syndrome and this can be followed by resolution of lung disease, persistent severe inflammatory lung injury, or fibrosis. The immune system, particularly at mucosal sites, is critical to resolve ongoing inflammatory responses but also to promote tissue repair. COVID-19 provides a unique opportunity to define how mucosal immunity mediates tissue damage, recovery, or aberrant fibrotic repair. Numerous immune cell populations have been shown to contribute to lung fibrosis in animal models and in human lungs. Most recently in convalescent COVID-19, T cell subsets, like CD8+ tissue resident memory cells and CXCR6+CD8+ cells have been associated with long term pulmonary sequelae. There is also an emerging literature that novel autoantibodies are formed early in acute COVID-19 particularly in hospitalized patients. Autoimmune disease is a known risk factor for the development of pulmonary fibrosis. This suggests a possible link between autoreactivity in COVID-19 and pulmonary sequelae of disease. In this study, the immune cell populations, proteins, and autoreactive changes will be studied to determine the important factors that contribute to aberrant lung repair in COVID-19. Previously collected tracheal aspirate and peripheral blood samples from patients with severe COVID-19 and contemporary controls with acute respiratory failure due to causes other than COVID-19 will be studied. The first aim will characterize immune cell subsets that associated with pulmonary fibrosis using high dimensional flow cytometry. The second aim will identify autoantibodies and autoreactive T cell populations that are present in the airway in patients with COVID-19 and whether development of autoreactivity associates with impaired pulmonary recovery. The third aim will utilize a next generation proteomics platform, SomaScan, to detect immune proteins that associate with the development of lung injury and fibrosis in COVID-19. Together, these studies will establish the key lung and circulating immune mediators of impaired pulmonary recovery and pulmonary fibrosis in COVID-19.