Cross-Species Comparison Reveals Molecular and Functional Novelty of Porcine Interferon-Omega Subtype

Abstract Innate immune interferons (IFNs), particularly type I IFNs, are primary mediators regulating antiviral immunity. These antiviral cytokines have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats. We have annotated IFN gene families across 155 animal genomes, and show that pigs have the largest and an expanding type I IFN family consisting of nearly 60 functional genes that encode seven IFN subtypes including multigene subtypes of IFN-α and -ω. Whereas subtypes such as IFN-α and -β have been widely studied, the unconventional IFN-ω subtype has barely been investigated. We have evolutionarily defined the porcine IFN family, and preliminarily showed that porcine IFN-ω subtype has evolved several novel features including, (1) a signature multi-gene subtype expanding particularly in bats and ungulates, (2) emerging isoforms that have much higher antiviral potency than typical IFN-α, (3) cross-species high antiviral (but little antiproliferative) activity in cells of humans and other mammalian species, and (4) potential action through noncanonical signaling pathways. This study is focused on antiviral potency of porcine IFN-ωs investigating their evolutionary and functional diversity, signaling specificity, and optimization of novel antivirals against devastating viral diseases. This project will, for the first time in an animal species, establish state-of-the-art procedures for efficient characterization of the molecular and functional spectrums of unconventional IFNs, which will further IFN-based novel antiviral design. Supported by grants from USDA (NIFA AFRI 2013-67015-21236 and NIFA AFRI 2015-67015-23216)