Hippo pathway activation drives fibrogenic remodelling in influenza A virus-infected lung fibroblasts

Abstract

Graphical abstract Influenza A virus (IAV) activates alveolar macrophages and directly engages Hippo signalling in lung fibroblasts, ultimately driving pulmonary fibrosis. YAP: Yes-associated protein; TAZ: transcriptional coactivator with PDZ-binding motif; TEAD: transcriptional enhanced associate domain; PAI: plasminogen activator inhibitor; CTGF: connective tissue growth factor. http://www.w3.org/1999/xlink float portrait 01123-2025.GA01.jpg anchor Graphical abstract GA1 portrait graphical abstract-1 Background Pulmonary fibrosis is a progressive and often fatal interstitial lung disease with largely undefined aetiology. Alveolar macrophages and lung fibroblasts play key roles in maladaptive tissue remodelling; however, the cellular and molecular mechanisms underlying their coordinated fibrotic responses remain incompletely characterised. Methods Following influenza A virus (IAV) infection, viral load, cytokine release and transcriptomic changes were analysed. To assess indirect effects on fibrosis, IMR-90 fibroblasts were treated with conditioned media from infected alveolar macrophage-like (AML) cells. Direct IAV infection of IMR-90 cells was also performed to evaluate changes in the Hippo signalling pathway and fibrotic marker expression using microarray and transcriptomic approaches. Results For the first time, AML cells were successfully infected with IAV, validating this model for studying pathogen-driven exacerbation of fibrosis in ageing lungs. Transcriptomic and protein-level analyses revealed that IAV promotes fibrogenesis in fibroblasts through two distinct mechanisms: 1) indirectly,pro-inflammatory and pro-fibrotic mediators released by infected macrophages; and 2) directly, through viral-induced modulation of the Hippo signalling pathway, resulting in upregulation of key fibrotic markers such as CTGF, fibronectin and collagen I. Conclusions These findings provide novel mechanistic insights into macrophage–fibroblast crosstalk in the context of viral infection and fibrosis. They suggest that dysregulation of these interactions contributes to the susceptibility of the ageing lung to fibrotic remodelling following respiratory viral infections and may inform future therapeutic interventions targeting Hippo pathway signalling. Shareable abstract Macrophage-derived mediators and fibroblast Hippo signalling are critical drivers of virus-induced fibrosis, revealing actionable pathways for therapeutic intervention https://bit.ly/4q6vOTa short abstract-2