Project Summary Apart from the acute illness caused by SARS-CoV-2, it is now clear that a significant percentage of patients develop long-term conditions post COVID-19, including systemic and respiratory symptoms. Given the catastrophic spread of SARS-CoV-2 infection globally, there are many individuals that recover from acute COVID-19 and develop permanent impairment in lung function which can cause exertional dyspnea, fatigue (due to chronic hypoxia), and other limitations. This number will become even larger as the pandemic continues to progress. Therefore, there is an urgent need to understand the mechanisms underlying the development of chronic respiratory sequelae of COVID-19 to develop preventive and therapeutic interventions. In this application, we aim to unravel the driving mechanisms and identify potential therapeutic targets of chronic lung sequelae following COVID-19. To achieve this goal, we propose two Specific Aims (SA) for the study. SA 1. Decipher cellular and molecular traits underlying chronic lung sequelae post-acute COVID-19. We will enroll a group of COVID-19 convalescents that are expected to develop chronic lung sequelae after prior severe acute disease and a control population that completely recovered from previous mild or non-symptomatic COVID-19 infection. We will conduct comprehensive clinical examination supplemented by quantitative chest CT imaging and pulmonary function testing to determine clinical and pathophysiological characteristics of the two populations. We will collect longitudinal blood and bronchoalveolar lavage fluid (BAL) to obtain immune, molecular, and viral profiles in COVID-19 convalescents and controls. This unique approach integrating systemic and respiratory clinical, pathophysiological, cellular, molecular, and viral profiles of control or COVID- 19 convalescents will be highly compelling for future druggable target discovery. SA2. Model and validate targets of chronic lung sequelae post-acute COVID-19 in an animal model. We will establish a mouse model of chronic lung sequelae post-acute COVID-19. We will characterize systemic and respiratory host cellular and molecular responses in the model. integrate mouse and human data for validation of mechanistic links and discovery of new insights and/or targets for therapeutic interventions. We will then use the model to test whether target dysregulated respiratory CD8+ T cell responses could ameliorate chronic lung sequelae post-acute COVID-19. We will employ system biology tools to The successful completion of the study will generate unprecedented insights on clinical, viral, and immune traits of pulmonary sequelae, and will identify key causal immune mechanisms and therapeutic targets against chronic lung diseases post-acute COVID-19.