tetano
Editor, Senior Moderator
Am J Respir Cell Mol Biol
. 2026 Mar 23:aanag057.
doi: 10.1093/ajrcmb/aanag057. Online ahead of print.
Temporal Type I IFN Signaling Orchestrates Protective and Pathogenic Inflammation Post-Influenza
Md Bashir Uddin[SUP] 1 2 [/SUP], Michael McKelvey[SUP] 3 [/SUP], Sunil Palani[SUP] 1 4 [/SUP], Shengjun Shao[SUP] 1 [/SUP], Yuejin Liang[SUP] 1 [/SUP], Keer Sun[SUP] 1 [/SUP]
Affiliations
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 (MRSA) 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.
. 2026 Mar 23:aanag057.
doi: 10.1093/ajrcmb/aanag057. Online ahead of print.
Temporal Type I IFN Signaling Orchestrates Protective and Pathogenic Inflammation Post-Influenza
Md Bashir Uddin[SUP] 1 2 [/SUP], Michael McKelvey[SUP] 3 [/SUP], Sunil Palani[SUP] 1 4 [/SUP], Shengjun Shao[SUP] 1 [/SUP], Yuejin Liang[SUP] 1 [/SUP], Keer Sun[SUP] 1 [/SUP]
Affiliations
- PMID: 42089309
- DOI: 10.1093/ajrcmb/aanag057
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 (MRSA) 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.