Discovery and characterization of bat interferon stimulated genes as antiviral agents against highly pathogenic bat origin coronaviruses

Bat species are being increasingly recognized as reservoirs of emerging viruses such as coronaviruses (SARS-CoV, SARS-CoV-2, and MERS-CoV), filoviruses (Ebola and Marburg virus), and paramyxoviruses (Nipah and Hendra viruses), among others. Bats that are naturally or experimentally infected with these viruses do not demonstrate clinical signs of disease, whereas other mammals, such as humans develop severe disease. We and others have shown that bat species have evolved a refined antiviral response which is characterized by: (1) low and controlled pro-inflammatory response, and (2) a robust interferon (IFN) mediated antiviral response. Type I IFNs are the first line of defence against invading viruses and they enact their effect by upregulating antiviral interferon stimulated genes (ISGs). Based on our previous studies, we will mechanistically characterize potent bat ISGs against bat derived highly pathogenic human betacoronaviruses (beta-CoVs), such as MERS-CoV and SARS-CoV-2. We hypothesize that bat species have evolved ISGs that potently restrict beta-CoV replication and are resistant to inactivation by viral proteins. We will stimulate the production of ISGs in novel bat cell lines and in vivo in five species of bats (Eptesicus fuscus, Carollia perspicillata, Pteropus alecto, Rousettus aegyptiacus, and Eidolon helvum) that are known to carry viruses with human infection potential. We will characterize the 'interferome' in these bat species using bulk RNA sequencing and identify top ranked antiviral genes. Finally, we will express bat ISGs and assess their antiviral efficacy and functional domains against SARS-CoV-2 and MERS-CoV. Understanding how bats tolerate infections with highly pathogenic coronaviruses will inform strategies to develop novel therapeutics for humans.