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Principal Investigator: Jie Sun
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $662,044
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Active Follow-up><Acute><Acute Disease><Address><Adult><Adult Human><Age Years><Animal Model><Animal Models and Related Studies><Automobile Driving><Blood><Blood Reticuloendothelial System><Body Tissues><Breathlessness><Bronchoalveolar Lavage Fluid><CAT scan><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID-19><COVID-19 infection><COVID-19 sequelae><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><Characteristics><Chronic><Chronic Lung Injury><Chronic Pulmonary Injury><Chronic lung disease><Clinical><Clinical Research><Clinical Study><CoV-2><CoV2><Computed Tomography><Coronavirus Infectious Disease 2019><Development><Dyspnea><Enrollment><Exertion><Exhibits><Fatigue><Fibrosis><Future><Goals><Hospital Admission><Hospitalization><Human><Human Characteristics><Human Nature><Hypoxia><Hypoxic><Immune><Immune response><Immunes><Immunological response><Immunology><Impairment><Individual><Infection><Intervention><Intervention Strategies><LYT3><Lack of Energy><Link><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Long-term cohort><Longitudinal cohort><Longterm cohort><Lung><Lung Function Tests><Lung Respiratory System><Lung immune response><Memory><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Oxygen Deficiency><PASC><Pathologic><Patients><Physiologic><Physiological><Population><Population Control><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Preventative intervention><Pulmonary function tests><Resolution><Respiratory Signs and Symptoms><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 sequelae><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sample Size><Science><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Shortness of Breath><Study models><Survivors><System><Systems Biology><T cell response><T-Cell Subsets><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><Testing><Therapeutic Intervention><Time><Tissues><Tomodensitometry><Validation><Viral><Viral reservoir><Virus reservoir><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><active followup><acute COVID-19><acute SARS-CoV-2 infection><acute disease/disorder><acute disorder><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><adulthood><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><aged><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><airway symptom><catscan><chest CT><chest computed tomography><chronic COVID><chronic COVID-19><chronic COVID-19 sequelae><chronic novel coronavirus disease 2019><chronic pulmonary disease><clinical exam><clinical examination><cohort><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><data integration><developmental><driving><druggable target><enroll><follow up><follow-up><followed up><followup><hCoV19><high risk><host response><human data><immune system response><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><intervention for prevention><intervention therapy><interventional strategy><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term sequelae><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><lung function><model of animal><mortality><mouse model><murine model><nCoV2><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pandemic><pandemic disease><pathogen><persistent COVID-19><population aging><post COVID syndrome><post COVID-19 sequelae><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute sequelae following COVID-19><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-COVID><post-COVID-19><post-acute phases of COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><post-coronavirus disease 2019><predictive biomarkers><predictive marker><predictive molecular biomarker><prevention intervention><preventional intervention strategy><preventive intervention><prolonged COVID-19 symptoms><pulmonary><pulmonary function><pulmonary immune response><resident memory T cell><resolutions><respiratory><respiratory symptom><response><sequelae following COVID-19><sequelae following SARS-CoV-2 infection><sequelae of COVID-19><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tissue resident memory T cell><tool><trait><validations>