Understanding and targeting fibroblast activation in influenza-triggered lung inflammation and post-viral disease

项目总结 流感病毒感染引发肺部炎症和病理，是急性呼吸道疾病的主要原因。 窘迫综合症。病毒清除后，肺部炎症和病理可持续存在，阻碍康复。 从严重的感染病例中。这种持续性的肺部炎症和病理，也称为病毒后 肺部疾病(PVLD)是流感病毒感染被低估的一个方面，即使许多患者 住院时间延长，25%-50%的患者持续出现呼吸道症状 出院后至少2个月。严重的流感病毒感染也会加剧其他慢性 呼吸系统疾病，包括慢性阻塞性肺病和特发性肺纤维化。目前，没有审批通过的 药物干预，以提高病毒清除后的恢复和预防或逆转PVLD及其 长期影响。PVLD的特征是肺组织中持续存在炎性免疫细胞。 有效的肺泡上皮修复失败，能够恢复组织功能。蜂窝和/或 驱动炎性免疫细胞持续存在和预防有效肺泡形成的分子机制 在没有正在进行的病毒复制的情况下进行修复是未知的。我们最近发现肺成纤维细胞是 炎症和流感疾病严重程度的驱动因素。我们展示了肺成纤维细胞的一个谱系，我们 术语炎性成纤维细胞(IFibs)，在推动发病机制方面尤为重要，而且不仅促进 炎症过度，但也防止在急性感染期间恢复正常的肺泡功能。我们的 初步数据现在表明，这些ifib在感染的急性期不会死亡，但 相反，它会持续到流感病毒感染后的阶段。总而言之，这些数据允许我们假设一个 肺成纤维细胞亚群在急性IAV感染期间存活于调节细胞死亡，分化为激活 Ifibs，在病毒清除后很好地保持在受损的肺组织中，并通过持续产生 炎症介质。我们将通过解决以下三个关键问题来验证这一假设：(1)来自 驱动PVLD的炎性成纤维细胞在哪些细胞以及何时出现？(2)炎性成纤维细胞持续存在吗？ 因为它们不经历调节的细胞死亡，以及(3)抑制的治疗潜力是什么 PVLD中持续的炎性成纤维细胞活性？该项目的成功完成将确定一个独特的 炎性肺成纤维细胞作为启动和驱动PVLD的细胞类型及其机制 他们在感染后的坚持性。这项研究将确定新的治疗切入点，以预防或 在PVLD发展到不可逆转的程度之前减少它。

PROJECT SUMMARY Influenza virus infection triggers lung inflammation and pathology and is a leading cause of acute respiratory distress syndrome. Following viral clearance, lung inflammation and pathology can persist preventing recovery from severe cases of infection. Such persistent lung inflammation and pathology, also referred to as Post-viral Lung Disease (PVLD), is an underappreciated aspect of influenza virus infections, even though many patients suffer extended hospital stays, and 25 – 50% of patients continue to experience respiratory symptoms for at least 2 months after hospital discharge. Severe influenza virus infections also exacerbate other chronic respiratory diseases, including COPD and idiopathic pulmonary fibrosis. Currently, there are no approved pharmacologic interventions to improve recovery after viral clearance and to prevent or reverse PVLD and its long-term effects. PVLD is characterized by the persistence of inflammatory immune cells in the lung tissue and the failure of effective alveolar epithelial repair capable of restoring tissue function. The cellular and/or molecular mechanisms driving the persistence of inflammatory immune cells and preventing effective alveolar repair in the absence of ongoing viral replication are not known. We recently identified lung fibroblasts as drivers of inflammation and influenza disease severity. We showed that a lineage of lung fibroblasts, which we term inflammatory fibroblasts (iFibs), are especially important for driving pathogenesis, and not only promote hyperinflammation, but also prevent restoration of normal alveolar function during acute infections. Our preliminary data now demonstrate that these iFibs do not die during the acute phase of the infection, but instead persist into post-viral stages of influenza disease. Together, these data allow us to hypothesize that a subset of lung fibroblasts survives regulated cell death during acute IAV infection, differentiate into activated iFibs, persist in damaged lung tissue well after viral clearance, and drive PVLD by continued production of inflammatory mediators. We will test this hypothesis by addressing the following three key questions: (1) From which cells, and when, do PVLD-driving inflammatory fibroblasts arise? (2) Do inflammatory fibroblasts persist because they do not undergo regulated cell death, and (3) What is the therapeutic potential of inhibiting persistent inflammatory fibroblast activity in PVLD? Successful completion of this project will identify a distinct lineage of inflammatory lung fibroblasts as the cell type that initiates and drives PVLD and the mechanism of their persistence following infection. This research will identify novel therapeutic entry points to prevent or reduce PVLD before it develops to the point that it becomes irreversible.