<i>Irf7</i> Deficiency Confers Protection Against Influenza Infection, Independent of <i>irf3</i>

Interferon regulatory factors <i>irf3</i> and <i>irf7</i> are pivotal for antiviral immunity, yet their cell-type-specific contributions, particularly within macrophage and dendritic cell (DC) lineages, have not been fully elucidated. Here, employing a multi-omics strategy encompassing <i>in vitro</i> assays, <i>in vivo</i> influenza A virus (IAV) infection models, NanoString, transcriptomic analyses, and scGPT-based computational modeling, we dissect the divergent and context-dependent roles of <i>irf3</i> and <i>irf7</i>. We demonstrate macrophages exhibit heightened sensitivity to TLR3 stimulation, a response critically dependent on <i>irf3</i>. Conversely, DCs respond more robustly to TLR7 activation and very weakly to TLR3 activation. Unexpectedly, global <i>Irf7</i> ^-/- mice displayed enhanced survival against IAV-induced lethality, whereas global <i>Irf3</i> ^-/- mice exhibited similar mortality to WT mice but demonstrated accelerated physiological recovery during the resolution phase, indicative of reduced disease severity rather than improved survival. Deep transcriptomic profiling of lung alveolar macrophages (AM), DC1, and DC2 subsets revealed distinct <i>irf3</i> and <i>irf7</i> dependent gene programs, with <i>irf7</i> prominently driving responses in AM and DC2 populations post-IAV infection. Furthermore, scGPT simulations predicted <i>irf3</i>-associated regulation of pathways like IL-17 signaling distinct from <i>irf7</i>-biased control over Th17 differentiation and JAK-STAT signaling, suggesting a model where <i>irf3</i> mainly drives rapid pathogen sensing and defence, whereas <i>irf7</i> regulates sustained inflammation and adaptive immune coordination. Cross-species analyses confirmed conserved and divergent <i>irf3</i>/<i>irf7</i> activities in human myeloid cells. Our findings provide a detailed framework of <i>irf3</i>/<i>irf7</i> cell-specific functions, illuminating their nuanced interplay in orchestrating antiviral defence and offering potential targets for immunomodulation. This knowledge may inform the development of targeted antiviral therapeutic strategies and contribute to a more nuanced understanding of innate immune regulation.