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

摘要/摘要 严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)已导致一种名为新冠肺炎的呼吸系统疾病在国际上暴发。新冠肺炎感染预后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。目前和新出现的数据表明，严重新冠肺炎感染的幸存者可能会出现肺纤维化和持续的肺功能损害。鉴于SARS-CoV-2感染的潜在灾难性传播，这里预测将有大量人从严重的新冠肺炎感染中康复，并因肺纤维化而出现永久性的肺功能损害。然而，目前还没有预防手段或治疗干预措施来减缓和/或逆转任何病毒性肺炎后的肺纤维化发展。我们假设，严重新冠肺炎感染的老年幸存者即使在急性感染完全缓解后，也会因肺纤维化而出现持续性的肺功能损害。此外，我们假设恢复的患者将出现肺纤维化，他们的呼吸道中CD8 TRM细胞的存在和/或CD8 TRM细胞上CD38的表达增强，从而导致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的目标。具体目的1：检测严重SARS-CoV2感染后呼吸道CD8-TRM细胞水平和肺纤维化定量评分。目的：确定靶向CD8 TRM细胞和/或CD38通路是否能减轻重症病毒性肺炎老年存活者的病毒后肺纤维化和保护肺功能。如果成功，我们期望这项研究将确立CD8TRM细胞在新冠肺炎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CD38Ab，特异性阻断CD38胞外酶功能，作为一种治疗康复的新冠肺炎肺纤维化患者的新方法。

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.