PROJECT SUMMARY As of the submission of this proposal, over 38 million cases of COVID-19 including a million deaths have been reported worldwide. COVID-19 is a respiratory disease caused by the novel coronavirus SARS-CoV-2 that can range from a mild to a severe/fatal disease characterized by excessive lung inflammation, acute respiratory distress syndrome (ARDS), coagulopathy, and multi-organ failure. Current studies suggest a major role for myeloid cell subsets in the development and exacerbation of disease, but the precise roles of lung-resident macrophages and infiltrating monocytes in COVID-19 pathogenesis remains poorly understood. It is already well-established that chronic heavy alcohol drinking (CHD) is a significant risk factor for developing ARDS and admission to the intensive care unit (ICU) for patients with pneumonia. CHD is also associated with increased susceptibility to both bacterial and viral pulmonary infections, notably respiratory syncytial virus (RSV), community-acquired pneumonia, and tuberculosis. Defects in epithelial barrier as well as anti-microbial functions of alveolar macrophage are believed to be major causes for increased vulnerability to respiratory diseases in individuals with CHD. Despite the clear association between CHD and increased risk of severe pulmonary infections, no studies to date have examined the impact of CHD on the immune response to SARS-CoV-2. In this application, we propose to test the hypothesis that chronic alcohol drinking alters lung-resident myeloid cells leading to exacerbated inflammatory response to SARS-CoV-2 with reduced viral clearance. To test this hypothesis, we will leverage a rhesus macaque model of voluntary ethanol self- administration that accurately mirrors human physiology and recapitulates complex human drinking behavior. Using this model, we recently demonstrated that CHD results in transcriptional and epigenetic rewiring of circulating monocytes and splenic macrophages, resulting in aberrant inflammatory responses. Additional preliminary studies show enhanced production of inflammatory factors with reduced type I IFN response to RSV infection as well as decreased phagocytic capacity of alveolar macrophages in CHD animals. We will first examine the impact of CHD on the phenotypic, functional and transcriptional landscape of lung-resident immune cells. Then, we will examine the impact of CHD on the response of lung-resident immune cells to SARS-CoV-2 infection. Completion of these experiments will allow us to define CHD-mediated differences in the lung immune response to SARS-CoV-2 infection that modulate COVID19 disease progression and severity.