The Airway Microbiome as a Modulator of Influenza Virus Infection: Mechanistic Insights and Translational Perspectives—Review

Outcomes of influenza virus infection vary widely across individuals, reflecting not only viral genetics and host factors but also the composition and function of the airway microbiome. Over the past few years, mechanistic work has clarified how specific commensals (for example, <i>Staphylococcus epidermidis</i> and <i>Streptococcus oralis</i>) restrict influenza replication by priming epithelial interferon-λ programs, reshaping intracellular metabolite pools (notably polyamines), dampening host protease activity, and maintaining barrier integrity; meanwhile, pathobionts (notably <i>Staphylococcus aureus</i> and <i>Streptococcus pneumoniae</i>) can enhance viral fitness via secreted proteases and neuraminidases that activate hemagglutinin and remodel sialylated glycoconjugates and mucus, setting the stage for secondary bacterial disease. Recent studies also highlight the gut-lung axis: gut microbiota-derived short-chain fatty acids (SCFAs), especially acetate, protect tight junctions and modulate antiviral immunity in influenza models. Together, these insights motivate translational strategies-from intranasal live biotherapeutics (LBPs) to metabolite sprays and decoy/dual neuraminidase approaches-that complement vaccines and antivirals. We synthesize recent evidence and outline a framework for leveraging the airway microbiome to prevent infection, blunt severity, and reduce transmission. Key priorities include strain-level resolution of commensal effects, timing/dosing windows for metabolites and LBPs, and microbiome-aware clinical pathways for anticipating and averting bacterial coinfection. Overall, the airway microbiome emerges as a tractable lever for influenza control at the site of viral entry, with several candidates moving toward clinical testing.