Extensive adaptive changes in bat interferon pathway reveal specific molecular functions at the forefront of host - virus coevolution

The interferon (IFN) response is a fundamental component of the mammalian innate immune system, orchestrating a broad antiviral state through a network of interferon-stimulated genes (ISGs). In bats, which are natural reservoirs for diverse viruses, several ISGs exhibit lineage-specific evolutionary adaptations, reflecting unique immune strategies. While previous research has typically focused on individual ISGs or broad-scale genomic analyses, here, we conducted an evolutionary analysis of type I IFN-upregulated genes across diverse bat species to elucidate the forces shaping the full repertoire of their ISG responses. Our results reveal that key components of bats antiviral signaling, including viral dsRNA sensors, PARP-mediated ADP-ribosylation enzymes, and cytokine/chemokine signaling molecules, have been recurrent targets of strong positive selection. Notably, immune sensors such as TLR3, RIG-I, and MDA5 show adaptive changes in their RNA-binding domains, suggesting modified viral recognition. Members of the PARP family exhibit repeated selection in both macro and catalytic domains, consistent with intense host - virus conflict and immune modulation. Strikingly, chemokine genes - especially CXCL10 and CXCL16 - and their receptors display some of the strongest and most 26 concerted selection signatures, particularly in ligand-binding loops, consistent with arms-race coevolution potentially driven by viral mimicry. Several positively selected genes have pleiotropic functions in tissue repair, inflammation, and tumor control, suggesting that some of these adaptations may influence several physiological pathways. Altogether, our findings uncover a bat-specific antiviral architecture shaped by concerted adaptive evolution, highlighting a balance between viral control and immune tolerance, likely underlying bats' exceptional resilience to disease.