Abstract
Influenza A virus (IAV) remains a global health threat, with severe cases causing high morbidity and mortality. Type I interferons (IFN-α/β) are crucial for early innate immunity to IAV but can drive immunopathology. This study investigates the role of heme oxygenase-1 (HO-1), a stress-responsive protein with anti-inflammatory properties, in modulating the immune response to IAV. Lung-tropic adeno-associated virus (AAV)-mediated HO-1 overexpression reduces lung damage by limiting immune cells infiltration, including plasmacytoid dendritic cells and classical monocytes, while promoting regulatory T cells (Tregs) and nonclassical monocytes. Additionally, HO-1 increases macrophage populations, enhancing antiviral responses via IFN pathways. Consistent with this, HO-1 knockout mice experience more severe infections, and HO-1 recruit inhibited IAV replication and alleviated pulmonary inflammation. In addition, compared with wide-type, the catalytically inactive mutation (H25A) impairs HO-1's anti-inflammatory function. These findings underscore HO-1's critical role in balancing antiviral immunity and inflammation, positioning it as a potential therapeutic target for severe influenza.