De La Cruz-Rivera, P. C. | Search bioRxiv

bioRxiv2024

IRF7 from the black flying fox induces a STAT1-independent ISG response in unstimulated cell lines that protects against diverse RNA viruses

Bats are considered unique in their ability to harbor large numbers of viruses and serve as reservoirs for zoonotic viruses that have the potential to spill over into humans. However, these animals appear relatively resistant to the pathogenic effects of many viruses. Mounting evidence suggests that bats may tolerate viral infections due to unique immune features. These include evolutionary innovations in inflammatory pathways and in the molecules involved in viral sensing, interferon induction, and downstream interferon-induced antiviral effectors. We sought to determine whether interferon-stimulated genes (ISGs) from the black flying fox (Pteropus alecto) encoded proteins with unique antiviral activity relative to their human orthologs. Accordingly, we compared the antiviral activity of over 50 ISG human-bat ortholog pairs to identify differences in individual effector functions. We identified IRF7 from Pteropus alecto (Pa.IRF7) as a potent and broad-acting antiviral molecule that provides robust antiviral protection without prior activation. We show that Pa.IRF7 uniquely induces a subset of protective ISGs independent of canonical IFN signaling, which leads to protection from alphaviruses, a flavivirus, a rhabdovirus, and a paramyxovirus. In uninfected cells, Pa.IRF7 partially localizes to the nucleus and can directly bind interferon-sensitive regulatory elements (ISREs). Compared to human IRF7, Pa.IRF7 also has additional serines in its C terminal domain that contribute to antiviral activity and may serve as unique phosphorylation hubs for activation. These properties constitute major differences between bat and human IRF7 that offer additional insight into the potential uniqueness of the black flying fox immune system.

immunology↗

bioRxiv2017

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.

immunology↗