Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract viral infection in infants and causes around 60,000 in-hospital deaths annually. Emerging evidence suggests that RSV induces metabolic changes in host cells to support viral replication, presenting a potential target for therapeutic intervention. To investigate RSV-driven metabolic changes in situ, we combined positron emission tomography (PET), live-cell bioenergetics, and metabolomic profiling in the upper and lower airways of children. PET imaging revealed persistent, hyper-glycolytic regions in the lungs of RSV-infected children. Bioenergetic analysis of freshly collected nasopharyngeal aspirates from infants showed live upper respiratory cells (URCs) infected with RSV in situ exhibited significantly higher levels of glycolysis, glycolytic capacity, glycolytic reserves, and mitochondrial respiration than uninfected controls. Metabolomic analysis of nasopharyngeal fluids from these patients revealed distinct metabolic signatures, including increased citrate and malate, and decreases in taurine. In vitro infection of pediatric nasopharynx tissue-derived multicellular epithelial cultures (TEpiCs) and bronchial epithelial cells further confirmed RSV-induced increases in glycolysis. Together, these findings demonstrate that RSV infection induces hypermetabolism in both upper and lower primary airways in situ, supporting the potential of host-targeted metabolic interventions as a therapeutic strategy-particularly in vulnerable populations such as infants for whom vaccines are not currently available.