Early metabolic reprogramming licenses Streptococcus pneumoniae for Influenza-driven superinfection

Abstract Bacterial pneumonia remains a major cause of morbidity and mortality following influenza A virus (IAV) infection. However, the adaptive mechanisms that enable pathogen expansion in the post-viral lung remain poorly defined. Here, using a mouse model of IAV–Streptococcus pneumoniae superinfection, we characterize bacterial transcriptional reprogramming in vivo. We identify alcohol dehydrogenases (AdhA and AdhE), that support NAD⁺ regeneration during mixed-acid fermentation, as key determinants of bacterial fitness specifically in the IAV-primed lung. Genetic deletion of these results in a pronounced fitness defect during superinfection but not in primary bacterial pneumonia. Consistent with this requirement, pharmacological inhibition of alcohol dehydrogenases limits bacterial expansion and dissemination following IAV infection. Mechanistically, we show that IAV infection profoundly remodels the lung environment, inducing hypoxia and increasing the availability of alternative carbon sources, which together impose a metabolic dependency on Adh for bacterial expansion. Our findings place metabolic adaptation as a central driver of pneumococcal outgrowth following viral infection and reveal exploitable vulnerabilities for therapeutic intervention. Competing Interest Statement The authors have declared no competing interest.