Bat-specific adaptations in interferon signaling and GBP1 contribute to enhanced viral tolerance

Bats are reservoirs of emerging zoonotic viruses of concern that cause severe disease in humans and agricultural animals. However, it is poorly understood how bats are able to tolerate diverse viral infections, knowledge that could help pave the way for new therapeutic strategies. Here, we characterized antiviral pathways in two divergent bat species, Pteropus alecto and Eptesicus fuscus, identifying unique bat-specific mechanisms underlying their enhanced antiviral tolerance. We demonstrate the critical roles of STAT1 and STAT2 in IFNβ signaling, along with species-specific adaptations that collectively contribute towards a “steady and ready” antiviral state in bat cells. Unlike in humans, we find that bat interferon signalling processes resist the immune antagonistic properties of viruses like MERS-CoV which further explains the ability of bats to tolerate coronavirus infections. Using transcriptomic analysis, we identified canonical and non-canonical interferon stimulated genes (ISGs) including two key bat genes, IFIT1 and GBP1. Compared to their human orthologs, we show that bat IFIT1 and GBP1 exhibit enhanced antiviral activity against a wide range of RNA and DNA viruses, including coronaviruses and additional bat-derived poxviruses (e.g., Eptesipoxvirus). Ultimately, our work provides important insights into the evolution of enhanced interferon-mediated antiviral responses in bats, contributing to their unique ability to resist viral diseases.