Respiratory syncytial virus G glycoprotein promotes Streptococcus pneumoniae-induced severe pneumonia

Objectives Co-infection with RSV and S.pn is linked to severe, often fatal pneumonia, with unclear molecular mechanisms. This study investigates whether RSV and S.pn interaction enhances pneumococcal pathogenicity and explores the underlying molecular mechanisms. Methods We co-incubated S.pn with RSV and transnasally infected mice, using RNA-seq and proteomics to analyze bacterial pathogenesis. Airway epithelial cells were infected with RSV and subsequently challenged with S.pn . We constructed an in vitro biofilm model for further study. Confocal microscopy and Western blotting investigated the association between the RSV G glycoprotein and S.pn . Mass spectrometry and pull-down assays identified surface proteins involved in direct binding. Results After incubation with RSV, S.pn exhibited a significant increase in inflammatory response and adherence to epithelial cells, as well as enhanced virulence in a murine pneumonia model. These effects were associated with extensive changes in the proteomics of S.pn and significantly upregulated expression of peptidoglycan biosynthesis genes. Additionally, we found that the RSV G glycoprotein binds to the maltodextrin ABC transporter substrate-binding protein of S.pn , which may explain how RSV infection enhances S.pn adhesion to cells. Conclusions The direct interaction between the RSV G glycoprotein and S.pn , leading to increased bacterial pathogenicity and more severe disease outcomes, represents a novel paradigm in respiratory infections. Clinical trial number Not applicable.