Antiviral restriction factors of bats: the front line of a critical reservoir of zoonotic viruses

Bats harbor diverse viruses pathogenic in other mammals, typically without obvious signs of clinical disease, attributed to an immune system that balances antiviral immunity with disease tolerance. It has been hypothesized that this balanced immune system may have arisen, at least in part, in response to the evolution of flight, which generates cellular stress, and subsequent selection for reduced inflammation and disease tolerance in bats. A major component of antiviral immunity is restriction factors (RFs). RFs are host cell proteins representing the first line of antiviral defense in all mammals, including bats. Here, we review recent advances in our understanding of bat RFs that have diversified compared to many of their counterparts in humans and other mammals. Across bat lineages, RF repertoires are repeatedly remodeled through shifts in basal and interferon-stimulated gene expression and expansions (e.g. APOBEC3, TRIM, IFITM, tetherin, GBPs). These diversified RFs target all major stages of viral replication. Bat-specific variations in RFs include residue- and isoform-dependent IFITM3 and tetherin functions, extensive APOBEC3 and TRIM gene locus rearrangements, as well as the presence of novel RFs, including a yet-to-be-identified RF that functions as a dominant, capsid-dependent nuclear-import block in pteropids, and RTP4 and RNF214 present in both bats and humans. Understanding these bat-adapted antiviral factors may inspire new approaches for host-directed therapeutics.