Discovery of Unique Antiviral Pathways in a Bat Viral Reservoir, the Black Flying Fox

Bats are asymptomatic reservoirs for a number of viral pathogens. How they manage to host highly pathogenic viruses such a Nipah and Marburg without showing clinical symptoms remains unclear. One of the earliest defenses vertebrates use to control viral infections is the interferon response. Upon viral infection, cells produce interferon which inhibits viral infection through downstream effectors called interferon stimulated genes. I questioned whether bat interferon stimulated genes contained unique properties that would make bats less susceptible to damage from viral infection. To address this, I used genetic tools to identify which interferon stimulated genes were expressed in cells from the black flying fox (Pteropus alecto). I found that RNASEL is uniquely induced in cells from the black flying fox, and that its activation is important for preventing viral infection. To determine if any bat interferon stimulated genes had evolved especially potent antiviral properties, I compared a group of bat and human interferon stimulated genes in a high-throughput format and discovered that bat IRF7 is more antiviral than human IRF7. Further studies demonstrated that bat IRF7 is active even in uninfected cells, and can induce a subset of protective antiviral genes without signaling through interferon. This function was in part due to unique serine residues at the C-terminal regulatory region of the protein that confer constitutive activity to bat IRF7. This work has uncovered two different mechanisms by which antiviral responses between bat and human hosts differ, and provides insight regarding how bats manage to keep numerous viral infections under control.