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>. The gene discussed is IRF7; the disease is influenza.