PROJECT SUMMARY/ABSTRACT Nearly one third of individuals who recover from acute COVID-19 will have chronic symptoms, so called ‘Post- Acute Sequelae of SARS-CoV-2’ infection (PASC). Among individuals with PASC, pulmonary complications such as persistent dyspnea and chronic cough are common. Although Native Hawaiians and Pacific Islanders (NHOPI) and Filipinos have been disproportionately affected by COVID-19, the prevalence and severity of pulmonary PASC (PPASC) among race/ethnicity is not known. As the number of individuals recovering from COVID-19 grows, PPASC is increasing with a devastating impact on patients, families and the healthcare system. Monocytes and monocyte-derived macrophages have been considered as key determinants of COVID-19 severity and respiratory failure. However, much less is known about their contribution to PPASC development, resolution, and disease persistence. The objective of the proposed project is to understand the pathophysiologic mechanisms of PPASC and how macro-social and psychological determinants are associated with these biological mechanisms. Our preliminary data showed that monocyte counts and CD169+ monocytes were significantly higher in PPASC compared to healthy individuals. Also, CD169+ non-classical monocytes were positively correlated with D-dimer levels in PPASC, suggesting that a specific monocyte subset and their activation may contribute to the disease severity. Our central hypothesis is that the development and persistence of PPASC is related to the influx of bone marrow-derived monocytes with proinflammatory phenotype into the lungs and is associated with macro-social and psychological determinants. To test this hypothesis, we propose the following Aims: (1) To understand monocyte dysregulation associated with the development and persistence of PPASC, particularly focusing on dynamic changes in the monocyte number, subpopulation, activation, and cytokines during the disease progression and resolution. (2) In a subset of the study cohort, to characterize the pathologic changes in respiratory system response to COVID-19. A detailed characterization of cell composition and cytokines in bronchoalveolar lavage (BAL) fluid will give an insight into monocyte activation and differentiation that is responsible for inflammatory dysregulation and fibrosis. (3) To examine the association of macro-social determinants (e.g., income and housing condition), and psychosocial factors (e.g., social isolation) with development of PPASC and changes in monocyte alteration. In summary, this is the first study to investigate the impact of macro-social and psychological determinants on clinical outcome in PPASC and the relationship between monocyte alteration in individuals with PPASC. Elucidating mechanisms in the role of monocytes in the pulmonary immunopathology of COVID- 19 will provide information for potential therapeutic interventions to ameliorate PPASC particularly among NHOPI and Filipinos.