COVID-19 competitive revision: BALANCING PROTECTIVE IMMUNITY AND CHRONIC SEQUELAE BY RESIDENT CD8 T CELLS

COVID-19 竞争性修订：平衡驻留 CD8 T 细胞的保护性免疫和慢性后遗症

• 批准号: 10224990
• 负责人: Jie Sun
• 金额: $ 21.16万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224990
• 关键词: 2019-nCoV; Ablation; Acute; Age; Animal Model; Animals; Antibodies; Attenuated; Blood Circulation; Bronchoalveolar Lavage; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; Cell Extracts; Cells; Cessation of life; Chest; Chronic; Clinic; Clinical; Clinical Data; Data; Development; Disease; Disease Outbreaks; Elderly; Enrollment; Exhibits; Expression Profiling; Fibrosis; Gene Expression Profiling; Immunity; Immunology; Impairment; Individual; Infection; Inflammation; Influenza; Injury; International; Literature; Lung; Lung diseases; Manuscripts; Measures; Mediator of activation protein; Memory; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patients; Phenotype; Pneumonia; Preventive; Pulmonary Fibrosis; Reporting; Residual state; Resolution; Respiratory System; Respiratory physiology; Role; Sampling; Science; Survivors; T memory cell; T-Cell Depletion; Testing; Therapeutic; Therapeutic Intervention; Tissues; Viral Pneumonia; Work; X-Ray Computed Tomography; acute infection; aged; antibody-dependent cell cytotoxicity; base; design; early phase clinical trial; lung development; lung preservation; mortality; mouse model; novel therapeutics; pneumonia model; pre-clinical; public health relevance; respiratory

Summary/Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an international outbreak of respiratory illness termed COVID-19. The primary determinant of outcome in COVID-19 infection is age, with the vast majority of morbidity and mortality occurring in the elderly. Current and emerging data suggests that survivors of severe COVID-19 infection will likely develop pulmonary fibrosis and persistent impairment of lung function. Given the potential catastrophic spreading of SARS-CoV-2 infection, it is predicted here that there will be a large number of individuals that recover from severe COVID-19 infection and develop permanent impairment in lung function due to lung fibrosis. However, there are no preventive means nor therapeutic interventions available to slow down and/or reverse lung fibrosis development following any viral pneumonia. We hypothesize that aged survivors of severe COVID-19 infection will develop persistent impairment of lung function due to pulmonary fibrosis even after complete resolution of acute infection. Furthermore, we hypothesize that recovered patients will pulmonary fibrosis will exhibit enhanced CD8 TRM cell presence in their respiratory tract and/or enhanced CD38 expression on CD8 TRM cells, contributing to tissue fibrosis and impaired lung function. To test these hypotheses, we have proposed two specific Aims in this study. Specific Aim 1: To determine respiratory CD8 TRM cell levels and quantitative lung fibrosis scores following severe SARS-CoV2 infection. Aim 2: To determine whether targeting CD8 TRM cells and/or CD38 pathway will attenuate post-viral pulmonary fibrosis and preserve lung function in elderly survivors of severe viral pneumonia. If successful, we expect that this study will establish an important role for CD8 TRM cells in lung fibrosis following COVID-19 pneumonia. Furthermore, this study will generate the necessary pre-clinical data to design early phase clinical trials using a new CD38 Ab that specific blocks CD38 ectoenzyme function as a novel therapy for recovered COVID-19 patients with lung fibrosis.

摘要/摘要 严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）已导致称为COVID-19的呼吸道疾病的国际爆发。COVID-19感染结局的主要决定因素是年龄，绝大多数发病率和死亡率发生在老年人中。目前和新出现的数据表明，严重COVID-19感染的幸存者可能会出现肺纤维化和肺功能持续受损。鉴于SARS-CoV-2感染的潜在灾难性传播，预测将有大量个体从严重的COVID-19感染中恢复，并因肺纤维化而发生永久性肺功能损害。然而，没有预防手段或治疗干预措施可用于减缓和/或逆转任何病毒性肺炎后的肺纤维化发展。我们假设，严重COVID-19感染的老年幸存者即使在急性感染完全消退后，也会因肺纤维化而出现持续性肺功能损害。此外，我们假设恢复的患者肺纤维化将在其呼吸道中表现出增强的CD 8 TRM细胞存在和/或增强的CD 8 TRM细胞上的CD 38表达，从而促进组织纤维化和肺功能受损。为了验证这些假设，我们在本研究中提出了两个具体目标。具体目标1：确定严重SARS-CoV 2感染后呼吸道CD 8 TRM细胞水平和定量肺纤维化评分。目标二：确定靶向CD 8 TRM细胞和/或CD 38通路是否会减轻重度病毒性肺炎老年幸存者的病毒后肺纤维化并保护肺功能。如果成功，我们预计这项研究将确立CD 8 TRM细胞在COVID-19肺炎后肺纤维化中的重要作用。此外，这项研究将产生必要的临床前数据，以设计早期临床试验，使用一种新的CD 38 Ab，特异性阻断CD 38胞外酶功能，作为一种新的治疗方法，用于恢复的COVID-19肺纤维化患者。