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

摘要/摘要 严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起了一场名为 COVID-19 的呼吸系统疾病的国际爆发。 COVID-19 感染结果的主要决定因素是年龄，绝大多数发病和死亡发生在老年人中。当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 感染可能发生灾难性传播，预计会有大量个体从严重的 COVID-19 感染中恢复过来，并因肺纤维化而出现肺功能永久性损伤。然而，没有预防手段或治疗干预措施可以减缓和/或逆转任何病毒性肺炎后肺纤维化的发展。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肺功能持续受损。此外，我们假设肺纤维化康复患者会表现出呼吸道中 CD8 TRM 细胞增强和/或 CD8 TRM 细胞上 CD38 表达增强，从而导致组织纤维化和肺功能受损。为了检验这些假设，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-CoV2 感染后呼吸道 CD8 TRM 细胞水平和定量肺纤维化评分。目标 2：确定针对 CD8 TRM 细胞和/或 CD38 通路是否会减轻严重病毒性肺炎老年幸存者的病毒后肺纤维化并保留肺功能。如果成功，我们预计这项研究将确定 CD8 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 CD38 Ab 特异性阻断 CD38 胞外酶功能，作为治疗患有肺纤维化的 COVID-19 康复患者的新疗法。

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.