The IFN response in bat cells consists of canonical and non-canonical ISGs with unique temporal expression kinetics

Bats are reservoirs for a number of highly pathogenic zoonotic viruses, yet they remain relatively asymptomatic during infection. Whether this viral resistance is due to a unique innate immune system is unknown. An evolutionarily conserved feature of vertebrate antiviral immunity is the interferon (IFN) response, which triggers cellular defenses through interferon-stimulated gene (ISG) expression. While bats encode an intact IFN system, global ISG expression patterns in bat cells are not well characterized. Here, we used RNA-Seq to assess the transcriptional response to IFN in cells derived from the bat Pteropus alecto (black flying fox). We show induction of more than 100 transcripts, most of which are canonical ISGs observed in other species. Kinetic gene profiling revealed that P. alecto ISGs fall into two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast to bat ISGs, human ISGs generally remained elevated for longer periods following IFN treatment, suggesting host-based differences in gene regulatory mechanisms. Notably, we also identified a small group of non-canonical bat ISGs, including an enzymatically active RNASEL that plays a role in controlling viral infection. These studies provide insight into the innate immune response of an important viral reservoir and lay a foundation for studies into the immunological features that may underlie unique virus-host relationship in bats.\n\nSignificance StatementBats are considered unique in their ability to resist disease caused by viruses that are often pathogenic in humans. While the nature of this viral resistance is unknown, genomic data suggest bat innate immune systems may be specialized in controlling these disease-causing viruses. A critical cell intrinsic antiviral defense system in vertebrates is the interferon response, which suppresses viral infection through induction of hundreds of interferon-stimulated genes (ISGs). In this study, we report the repertoire of ISGs and several unique features of ISG induction kinetics in bat cells. We also characterize induction and antiviral activity of bat RNASEL, which is induced by IFN in bat, but not human cells. These studies lay the foundation for discovery of potentially new antiviral mechanisms in bats, which may spur research into development of therapies to combat viral infection.