Temporal type I IFN signaling orchestrates protective and pathogenic inflammation post-influenza

Abstract Secondary bacterial pneumonia following influenza A virus (IAV) infection markedly exacerbates lung inflammation and contributes to acute respiratory distress syndrome (ARDS); however, the immunologic pathways that drive lung injury and determine protective versus pathogenic inflammation remain incompletely defined. Using a clinically relevant murine model of sublethal IAV infection followed by methicillin-resistant Staphylococcus aureus challenge under antibiotic therapy, this study investigated the dynamic role of type I interferon (IFN-I) signaling in disease progression. The findings demonstrate that IFN-I exerts dual and contrasting effects on the host inflammatory response: it enhances myeloid-derived TNF-α while indirectly suppressing T cell–derived IFN-γ. Reporter mouse models identified recruited monocytes and dendritic cells (DCs) as the primary IFN-I–targeted populations, whereas neutrophils, T cells, and alveolar macrophages exhibited limited direct responsiveness. Myeloid-specific deletion of IFNAR1 reduced TNF-α production, restrained inflammatory monocyte differentiation, and improved survival without disrupting IFN-γ and IL-10 balance. Temporal IFNAR1 blockade further revealed that early IFN-I signaling supports alveolar macrophage maintenance and primes monocytes/DCs for immune activation, whereas sustained signaling during bacterial superinfection drives persistent monocyte chemoattractant production, excessive monocyte activation, and delayed resolution of inflammation. Collectively, these findings position IFN-I as a temporal immune rheostat—protective during acute viral infection but pathogenic when prolonged—and define a therapeutic window in which selective IFNAR inhibition enhances host antibacterial defense, either alone or in combination with antibiotic therapy. These insights highlight a promising immunomodulatory strategy to improve outcomes in severe viral–bacterial pneumonia and ARDS.