Respiratory syncytial virus-induced ADAM17 activity controls maintenance of epithelial barrier integrity and promotes syncytium formation.

Abstract

Respiratory syncytial virus (RSV) infection causes epithelial injury, barrier disruption, and formation of syncytia in human lung tissue; however, the regulatory host defense mechanisms involved remain poorly defined. ADAM17 is a multifunctional sheddase implicated in inflammatory lung disease and is considered a potential therapeutic target during viral infections. Here, we show that RSV infection induces ADAM17 activity through PKC- and ERK-dependent signaling, increasing surface ADAM17 levels and sheddase activity. Genetic loss or pharmacological inhibition of ADAM17 reduced RSV-induced formation of syncytia, post-entry viral spread, and viral titers. This identifies ADAM17 as a host factor that supports viral dissemination. ADAM17 deficiency simultaneously exacerbated RSV-induced epithelial injury, characterized by loss of intercellular cohesion, impaired barrier function, increased paracellular permeability, and enhanced cytotoxicity. RSV-induced ADAM17 activity promoted the release of multiple epithelial growth factor receptor (EGFR) ligands. Supplementation with recombinant amphiregulin partially restored barrier function in infected ADAM17-deficient cells. Consistent with these functional effects, ADAM17 deficiency was associated with the loss of epithelial differentiation-associated transcriptional programs and increased expression of inflammatory genes. These findings indicate that ADAM17 plays a dual role in RSV infection. It facilitates syncytial viral spread, while preserving epithelial integrity through autocrine EGFR signaling. Thus, ADAM17 activity represents a biological trade-off between viral dissemination and tissue protection, indicating that therapeutic ADAM17 inhibition may reduce viral spread at the cost of aggravating epithelial damage.IMPORTANCEDuring respiratory syncytial virus (RSV) infection, the airway epithelium must maintain barrier integrity while responding to virus-induced syncytium formation and tissue damage. It is poorly understood which host factors balance tissue preservation against viral replication and spread. Here, we demonstrate that the host cellular metalloproteinase ADAM17 is activated upon RSV infection. While RSV-induced ADAM17 activity promotes syncytium formation and viral spread, it concurrently controls the maintenance of epithelial barrier integrity, preserves cell survival, and inhibits hyperinflammatory signaling. By demonstrating that ADAM17 has a dual mode of action controlling both viral propagation and epithelial barrier resilience, this work uncovers a central trade-off: the same host factor exploited by RSV for dissemination is essential for protecting airway tissue. Consequently, targeting ADAM17 for antiviral therapy presents major challenges, as blocking viral spread may compromise vital epithelial defenses.