Rita Maria Quintela Tizon, Vaccine and Infectious Disease Organization / University of Saskatchewan

Rita Quintela1,2, Jacob Côté3, Victoria Gonzalez1,2, Vaidehee Lanke4, Jessica Wang1, Linfa Wang5, Andrew Doxey6, Sophie Gobeil3, Arinjay Banerjee1,2,6,7,8. 1Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, SK, Canada. 2Department of Veterinary Microbiology, University of Saskatchewan, SK, Canada. 3Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, QC, Canada. 4Department of Computer Science, University of Saskatchewan, SK, Canada. 5Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore. 6Department of Biology, University of Waterloo, ON, Canada. 7Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada. 8Department of Biochemistry and Molecular Biology, University of British Columbia, BC, Canada.

Discovering & Evolving

Bats are ancestral hosts of multiple zoonotic viruses, including betacoronaviruses (βCoVs) that cause severe disease and death in humans and livestock. Conversely, bats infected with these viruses do not show clinical signs of disease, making them a fascinating model to study the evolution of virus-host interactions. The innate immune response is the first line of defense against viral infections. Type I interferons (IFNs) are among the first cytokines to be released when an infection is detected in vertebrates. IFNs bind to the interferon-α/β receptor (IFNAR1/2) in host cells and induce the production of antiviral Interferon Stimulated Genes. βCoVs have evolved to impair type I IFN activity in humans, increasing our vulnerability to infections. However, little is known about how type I IFNs signal in bat cells and whether bats have evolved more efficient processes to better tolerate viral infections. We have identified that wildtype bat IFNβ does not protect human cells and vice versa, suggesting species-specific mechanisms. Based on positive selection analyses of IFNβ sequences from several mammals, we have produced mutated human and bat recombinant IFNβ, as well as recombinant bat IFNAR1/2, to test their binding and antiviral capabilities. In silico and experimental analyses including structural modelling and antiviral assays show that mutated IFNβ are unable to correctly interact with IFNAR1/2, resulting in weaker antiviral protection when compared to wildtype IFNβ. Our study identifies remarkable species-specific adaptation of IFNβ and downstream antiviral processes, which will inform basic and translational science for the development of IFNβ antiviral therapies for humans.