Accumulating evidence suggests that mammals also employ a diverse set ofIFN-I-independent antiviral defenses that likely operate alongside IFN-I responses.Many of these alternative defenses are ancient innate responses that predate therise of IFNs in jawed vertebrates during eukaryotic evolution but have been retainedin mammalian hosts to combat infection (11).We define IFN-I-independent antiviral immunity as defenses that do not rely oncanonical IFN or ISG production or those that induce ISGs but through non-canonicalsignaling pathways (1, 2). The gene discussed is IFNA1; the disease is infection.