Multiomics Identification and Validation of an Integrin–Extracellular Matrix Network Driving Respiratory Syncytial Virus‐Induced Lung Injury and Repair

ABSTRACT

Respiratory syncytial virus (RSV) is a major cause of severe lung injury, particularly in infants. Most previous studies have relied on single‐omics or single‐model systems, limiting a comprehensive understanding of the dynamic and coordinated host response. To overcome this, we employed an integrated multiomics approach across complementary in vivo (murine) and physiologically relevant ex vivo (human bronchial organoid) models, combining longitudinal transcriptomic and proteomic profiling to systematically delineate the spatiotemporal dynamics of RSV‐induced lung injury and repair. Our analysis revealed a stage‐specific progression from early inflammatory injury to late repair, in which extracellular matrix (ECM)–receptor interaction and PI3K–Akt signaling play central roles. Moreover, a core set of hub genes including Itgb3 , Itga2b , and Fn1 were positively correlated with RSV‐induced lung injury and clinical disease severity. Pharmacological inhibition of αIIbβ3 (encoded by Itga2b and Itgb3 ) or fibronectin ( Fn1 ) in vivo significantly attenuated immunopathology and lung injury without affecting viral clearance, directly establishing their causal role in disease pathogenesis. Collectively, our study not only provides novel insights into the integrin‐centric network driving RSV immunopathology but also identifies a potential biomarker panel for clinical severity stratification and therapeutic targets for intervention.