The vertebrate interferon (IFN) response controls viral infections by inducing hundreds of interferon-stimulated genes (ISGs), many of which encode ‘restriction factors’ that uniquely target certain viruses. ISG studies have historically had a human-centric focus, which is justified because these natural defense mechanisms might be leveraged to treat human viral disease. However, certain mammals are reservoirs for zoonotic viruses that can ‘spill over’ into humans. Additionally, restriction factors have prominent roles in the ongoing evolutionary genetic conflicts between viruses and their hosts. Thus, there is a growing need to understand antiviral IFN/ISG responses in other species, particularly in known reservoirs of zoonotic viruses. This review focuses on functional and evolutionary insight into antiviral IFN responses that have been obtained from studying non-model mammalian species.
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