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

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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.