In this study, we identified an uncovered, novel function of IFI6 in negatively regulating innate immune responses induced after infection with viruses belonging to different families (i.e. IAV, SARS-CoV-2, and SeV), as well as after poly(I:C) transfection, even in mice, using a novel IAV system to overexpress IFI6 in infected cells. The gene discussed is IFI6; the disease is infection.