Modulation of Lung Immune Responses to Viral Infection

修改后的项目摘要/摘要部分 严重的新冠肺炎一直与长期的肺部后遗症有关。严重新冠肺炎的患者会出现急性呼吸窘迫综合征，随后可能会出现肺部疾病的缓解、持续性的严重炎症性肺损伤或纤维化。免疫系统，特别是粘膜部位的免疫系统，对解决正在进行的炎症反应至关重要，也对促进组织修复至关重要。新冠肺炎提供了一个独特的机会来定义粘膜免疫如何介导组织损伤、恢复或异常的纤维化修复。在动物模型和人类肺中，大量的免疫细胞群被证明是导致肺纤维化的原因。最近，在新冠肺炎恢复期，T细胞亚群，如CD8+组织驻留记忆细胞和CXCR6+CD8+细胞与长期的肺部后遗症有关。也有新的文献表明，新的自身抗体在急性新冠肺炎的早期形成，特别是在住院的患者中。自身免疫性疾病是肺纤维化发展的已知危险因素。这表明新冠肺炎的自身反应性与疾病的肺部后遗症之间可能存在联系。在这项研究中，将研究免疫细胞群、蛋白质和自身反应性变化，以确定导致新冠肺炎异常肺修复的重要因素。先前从严重新冠肺炎患者和同期因新冠肺炎以外原因导致急性呼吸衰竭的对照组收集的气管抽吸物和外周血样将被研究。第一个目标将使用高维流式细胞术来表征与肺纤维化相关的免疫细胞亚群。第二个目标是确定新冠肺炎患者呼吸道中存在的自身抗体和自身反应性T细胞群，以及自身反应性的发展是否与肺恢复受损有关。第三个目标将利用下一代蛋白质组学平台SomaScan，检测与新冠肺炎肺损伤和纤维化发展相关的免疫蛋白。总之，这些研究将确定新冠肺炎患者肺功能受损和肺纤维化的关键肺和循环免疫介质。

Modified Project Summary/Abstract Section Severe COVID-19 has been associated with long term pulmonary sequelae. Patients with severe COVID-19 develop acute respiratory distress syndrome and this can be followed by resolution of lung disease, persistent severe inflammatory lung injury, or fibrosis. The immune system, particularly at mucosal sites, is critical to resolve ongoing inflammatory responses but also to promote tissue repair. COVID-19 provides a unique opportunity to define how mucosal immunity mediates tissue damage, recovery, or aberrant fibrotic repair. Numerous immune cell populations have been shown to contribute to lung fibrosis in animal models and in human lungs. Most recently in convalescent COVID-19, T cell subsets, like CD8+ tissue resident memory cells and CXCR6+CD8+ cells have been associated with long term pulmonary sequelae. There is also an emerging literature that novel autoantibodies are formed early in acute COVID-19 particularly in hospitalized patients. Autoimmune disease is a known risk factor for the development of pulmonary fibrosis. This suggests a possible link between autoreactivity in COVID-19 and pulmonary sequelae of disease. In this study, the immune cell populations, proteins, and autoreactive changes will be studied to determine the important factors that contribute to aberrant lung repair in COVID-19. Previously collected tracheal aspirate and peripheral blood samples from patients with severe COVID-19 and contemporary controls with acute respiratory failure due to causes other than COVID-19 will be studied. The first aim will characterize immune cell subsets that associated with pulmonary fibrosis using high dimensional flow cytometry. The second aim will identify autoantibodies and autoreactive T cell populations that are present in the airway in patients with COVID-19 and whether development of autoreactivity associates with impaired pulmonary recovery. The third aim will utilize a next generation proteomics platform, SomaScan, to detect immune proteins that associate with the development of lung injury and fibrosis in COVID-19. Together, these studies will establish the key lung and circulating immune mediators of impaired pulmonary recovery and pulmonary fibrosis in COVID-19.