Unconventional IFNx-like Genes Dominate the Type I IFN Locus and the Constitutive Antiviral Responses in Bats

Bats are the natural reservoir hosts of some viruses, some of which may spill over to humans and cause global-scale pandemics. Different from humans, bats may coexist with high pathogenic viruses without showing symptoms of diseases. As one of the most important first defenses, bat type I IFNs (IFN-Is) were thought to play a role during this virus coexistence and thus were studied in recent years. However, there are arguments about whether bats have a contracted genome locus or constitutively expressed IFNs, mainly due to species-specific findings. We hypothesized that because of the lack of pan-bat analysis, the common characteristics of bat IFN-Is have not been revealed yet. In this study, we characterized the IFN-I locus for nine Yangochiroptera bats and three Yinpterochiroptera bats on the basis of their high-quality bat genomes. We also compared the basal expression in six bats and compared the antiviral and antiproliferative activity and the thermostability of representative Rhinolophus bat IFNs. We found a dominance of unconventional IFN x-like responses in the IFN-I system, which is unique to bats. In contrast to IFN a-dominated IFN-I loci in the majority of other mammals, bats generally have shorter IFN-I loci with more unconventional IFN x-like genes ( IFN x or related IFN ax ), but with fewer or even no IFNa a genes. In addition, bats generally have constitutively expressed IFNs, the highest expressed of which is more likely an IFN x-like gene. Likewise, the highly expressed IFNx-like x-like protein also demonstrated the best antiviral activity, antiproliferative activity, or thermostability, as shown in a representative Rhinolophus bat species. Overall, we revealed pan-bat unique, to our knowledge, characteristics in the IFN-I system, which provide insights into our understanding of the innate immunity that contributes to a special coexistence between bats and viruses. The Journal of Immunology, , 2024, 213: 204-213.- 213.