Uncover mechanisms underlying the development of chronic lung sequelae post COVID-19

揭示 COVID-19 后慢性肺部后遗症发生的机制

• 批准号: 10734747
• 负责人: Jie Sun
• 金额: $ 72.03万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734747
• 关键词: 2019-nCoV; Acute; Acute Disease; Address; Adult; Age Years; Animal Model; Automobile Driving; Blood; Bronchoalveolar Lavage Fluid; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; Characteristics; Chronic; Chronic Lung Injury; Chronic lung disease; Clinical; Clinical Research; Development; Dyspnea; Enrollment; Exertion; Exhibits; Fatigue; Fibrosis; Future; Goals; Hospitalization; Human; Human Characteristics; Hypoxia; Immune; Immune response; Immunology; Impairment; Individual; Infection; Intervention; Link; Long COVID; Longitudinal cohort; Lung; Lung immune response; Memory; Modeling; Molecular; Morbidity - disease rate; Mus; Pathologic; Patients; Physiological; Population; Population Control; Post-Acute Sequelae of SARS-CoV-2 Infection; Pulmonary function tests; Resolution; Respiratory Signs and Symptoms; Role; SARS-CoV-2 infection; Sample Size; Science; Shortness of Breath; Study models; Survivors; System; Systems Biology; T cell response; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Time; Tissues; Validation; Viral; Viral reservoir; X-Ray Computed Tomography; aged; chest computed tomography; clinical examination; cohort; data integration; druggable target; follow-up; high risk; human data; insight; long-term sequelae; mortality; mouse model; new therapeutic target; pandemic disease; pathogen; post-COVID-19; predictive marker; preventive intervention; pulmonary function; respiratory; response; targeted treatment; therapeutic target; tissue resident memory T cell; tool; trait

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.

项目摘要 除了SARS-CoV-2引起的急性疾病外，现在很明显， 在COVID-19后出现长期状况，包括全身和呼吸道症状。鉴于 由于SARS-CoV-2感染在全球范围内的灾难性传播，许多人从急性 COVID-19并发生肺功能永久性损伤，可导致劳力性呼吸困难、疲劳（由于 慢性缺氧）和其他限制。随着这一流行病继续蔓延， 中求进工作总 因此，迫切需要了解发展的内在机制， COVID-19的慢性呼吸道后遗症 预防和治疗干预。 在这项应用中，我们的目标是解开驱动机制，并确定潜在的治疗目标，慢性 COVID-19后的肺部后遗症。为了实现这一目标，我们提出了两个具体目标（SA）的研究。sa 1.解读急性COVID-19后慢性肺后遗症的细胞和分子特征。 我们将 招收 一组COVID-19康复者，他们在之前严重的 急性疾病和对照人群，从先前的轻度或无症状完全恢复 COVID-19感染。我们将进行全面的临床检查，并辅以胸部定量检查 CT成像和肺功能检查，以确定临床和病理生理特征的 两个人口。我们将收集纵向血液和支气管肺泡灌洗液（BAL）以获得免疫， COVID-19康复者和对照组的分子和病毒谱。这种独特的方法整合了 控制或COVID的全身和呼吸系统临床、病理生理、细胞、分子和病毒特征 19康复期将是非常引人注目的未来可药用目标的发现。SA 2.建模和验证 急性COVID-19后慢性肺后遗症的靶点。我们将建立一个小鼠模型 急性COVID-19后的慢性肺部后遗症。我们将描述系统和呼吸宿主细胞和 模型中的分子反应。整合小鼠和人类数据， 验证机制联系和发现新的见解和/或治疗干预的目标。我们将 然后使用该模型来测试靶向失调的呼吸道CD8 + T细胞应答是否可以改善 急性COVID-19后的慢性肺部后遗症。 我们将使用系统生物学工具， 该研究的成功完成将产生对临床，病毒和免疫特征的前所未有的见解 肺后遗症，并将确定关键的因果免疫机制和治疗目标，对慢性 急性COVID-19后的肺部疾病。