Beyond IFNs: How IRFs suppress pathogenic inflammation during viral infection 2305581

Abstract

Abstract Introduction Type I interferon (IFN) responses are central to antiviral defense and are driven by IFN regulatory factors (IRFs), which are classically known as transcription factors that induce IFNs and antiviral genes. Our work identifies non-transcriptional activities of IRF3 and IRF7, including IRF3-dependent apoptosis of virus-infected cells and a distinct mechanism that suppresses NF-κB—driven inflammatory gene induction. These pathways shape the host response to viral infection and modulate immunopathology. Methods We used primary bone marrow-derived macrophages, IRF3/IRF7 transcriptionally inactive mutants, and IRF3 single-action (transcriptionally inactive) knock-in mouse models to dissect non-canonical IRF functions. NF-κB activity was assessed by cytokine expression by qRT-PCR, and protein interactions by immunoprecipitation and proximity ligation assay. In vivo relevance was evaluated in parainfluenza virus infection models using physiological and inflammatory readouts. Viral antagonism was examined through interaction and functional inhibition assays. Results IRF3 displayed two transcription-independent effector functions: induction of apoptosis in infected cells and direct repression of NF-κB-dependent inflammatory gene expression (RIKA). This anti-inflammatory IRF3 activity in macrophages was essential for protection against viral lung inflammation in mice. IRF7, which contains a similar NF-κB—binding motif, also suppressed inflammatory gene induction, revealing a broader non-canonical regulatory module within the IRF family. Several viral proteins selectively blocked this IRF:NF-κB interaction, demonstrating an evolved viral strategy to overcome IRF-mediated inflammation control. Conclusion IRF3 and IRF7 function beyond transcriptional activities to restrain inflammatory signaling and limit viral immunopathology. The newly defined non-canonical IRF pathways represent critical determinants of antiviral inflammation, targets of viral antagonism, and offer new avenues for therapeutic modulation. Funding Source NIH Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)