Eosinophil Activation in the Allergic Lung Limits Pneumococcal Superinfection During Influenza 2267175

Abstract Introduction Respiratory co-infections with influenza A virus (IAV) and Streptococcus pneumoniae (Spn) drive severe morbidity and mortality during influenza pandemics; however, epidemiologic data from 2009 revealed that individuals with allergic asthma and IAV infection were paradoxically less likely to develop bacterial pneumonia, require ICU care, or die compared to influenza patients without asthma. Methods We developed a triple-disease murine model that recapitulates this protection and investigated the underlying mechanisms. Results Allergic mice co-infected with IAV and Spn maintained body weight, had significantly reduced lung bacterial load, and exhibited less tissue inflammation and epithelial injury compared to non-allergic controls. The allergic lung is characterized by increased eosinophils and preserved alveolar macrophages during influenza. Eosinophils were activated by viral exposure, upregulating CD69, ICAM-1 and IL-5Rα, maintaining viability, and displaying heightened phagocytosis through receptor-mediated uptake and bacterial killing without cytolysis or extracellular trap formation. Macrophages from allergic mice retained antibacterial killing capacity following IAV infection, in contrast to macrophage depletion observed in non-allergic hosts. Antibiotic depletion of airway eosinophils and macrophages abrogated this protection, demonstrating that these innate cells cooperate to counter viral-bacterial synergy. Conclusion Together, these findings identify eosinophils as direct antiviral and antibacterial effectors that maintain barrier protection and limit bacterial superinfection. Our data suggest that allergic inflammation uniquely “pre-arms” eosinophils and sustains macrophage function, creating a lung microenvironment more resistant to lethal viral-bacterial co-infection. Ongoing work is focused on dissecting molecular pathways that license these eosinophil responses and translating this biology toward host-directed therapeutic strategies. Funding Source R01 HL171137 and the American Lung Association Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)