The soluble G protein of respiratory syncytial virus promotes viral dissemination via TLR2-mediated NLRP3 priming and pyroptosis

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections in infants, immunocompromised individuals, and older adults. Although vaccines and monoclonal antibodies have recently become available, understanding RSV pathogenesis remains essential for next-generation therapeutic strategies. RSV attachment glycoprotein G mediates virus binding through a CX3C-like chemokine motif, and its secreted soluble form (sG) possesses immunomodulatory properties. We showed that recombinant sG binds TLR2, inducing proinflammatory mediators. In vitro, sG pretreatment of airway epithelial cells enhanced viral replication upon infection, indicating functions beyond canonical receptor binding. We demonstrated that RSV sG can activate MyD88-NF-κB signalling in uninfected cells via TLR2, leading to NLRP3 upregulation and ROS accumulation. Subsequent RSV infection provides the second signal for caspase‑1 activation and pyroptosis, preconditioning neighbouring cells for inflammasome-dependent lysis and viral egress. Targeting the sG-TLR2 interface could reduce inflammatory damage and viral spread, providing a rationale for CX3C motif-directed interventions and NLRP3 inhibitors during infection.