Abstract
Interferon regulatory factors irf3 and irf7 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 in vitro assays, in vivo influenza A virus (IAV) infection models, NanoString, transcriptomic analyses, and scGPT-based computational modeling, we dissect the divergent and context-dependent roles of irf3 and irf7. We demonstrate macrophages exhibit heightened sensitivity to TLR3 stimulation, a response critically dependent on irf3. Conversely, DCs respond more robustly to TLR7 activation and very weakly to TLR3 activation. Unexpectedly, global Irf7 (-/-) mice displayed enhanced survival against IAV-induced lethality, whereas global Irf3 (-/-) 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 irf3 and irf7 dependent gene programs, with irf7 prominently driving responses in AM and DC2 populations post-IAV infection. Furthermore, scGPT simulations predicted irf3-associated regulation of pathways like IL-17 signaling distinct from irf7-biased control over Th17 differentiation and JAK-STAT signaling, suggesting a model where irf3 mainly drives rapid pathogen sensing and defence, whereas irf7 regulates sustained inflammation and adaptive immune coordination. Cross-species analyses confirmed conserved and divergent irf3/irf7 activities in human myeloid cells. Our findings provide a detailed framework of irf3/irf7 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.