Cross-species genome-wide analysis reveals molecular and functional diversity of the unconventional interferon-omega subtype

Authors: SHIELDS, LAUREN - Tennessee State University; LIU, QINFANG - Kansas State University; LEE - Kansas State University; MA, WENJUN - Kansas State University; BLECHA, FRANK - Kansas State University; Miller, Laura; SANG, YONGMING - Tennessee State University

Submitted to: Frontiers in Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/6/2019
Publication Date: 6/25/2019
Citation: Shields, L.E., Liu, Q., Lee, Ma, W., Blecha, F., Miller, L.C., Sang, Y. 2019. Cross-species genome-wide analysis reveals molecular and functional diversity of the unconventional interferon-omega subtype. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2019.01431.
DOI: https://doi.org/10.3389/fimmu.2019.01431

Interpretive Summary: Interferons (IFN) are in the center of antiviral immunity and have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats in the frontline. However, to date, only a few subtypes (e.g., IFN-alpha and IFN-beta) have been characterized at the molecular and functional level. This is a significant knowledge gap considering the evolutionarily diversified 20-60 IFN functional genes of multiple subtypes in each mammalian species. We have annotated IFN gene families across 110 animal genomes. Our efforts affiliated with the swine genome project have identified a phylogenic expansion of porcine innate immune IFNs that has resulted in 60 functional genes encoding at least 42 distinct peptides across seven subtypes. With multiple species-specific IFN subtypes in the cohort of IFN gene expansion, pigs are a crucial model for addressing the dynamic expression and functional spectrum of IFNs.

Technical Abstract: Innate immune interferons (IFNs), particularly type I IFNs, are primary mediators regulating animal antiviral, antitumor, and cell-proliferative activity. These antiviral cytokines have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats and physiological regulation. We have annotated IFN gene families across 110 animal genomes, and showed that IFN genes, after originating in jawed fishes, had several significant evolutionary surges in the vertebrate species of amphibians, bats and ungulates, particularly pigs and cattle. For example, 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-alpha, -delta and -omega. Whereas subtypes such as IFN-alpha and -beta have been cross-species widely studied, the unconventional subtypes such as IFN-omega has barely been investigated. We have evolutionarily cross-species defined the IFN complex, and showed that unconventional IFN subtypes particularly IFN-omega subtype has evolved several novel features including: (1) being a signature multi-gene subtype expanding particularly in mammalians such as bats and ungulates, (2) emerging isoforms that have superior antiviral potency than typical IFN-alpha, (3) highly cross-species antiviral (but little anti-proliferative) activity exerted in cells of humans and other mammalian species, and (4) demonstrating potential novel molecular and functional properties. This study is focused on IFN-omega as an example to investigate the immunogenetic evolution and functional diversity of unconventional IFN subtypes, which will further IFN-based novel antiviral design pertinent to their cross-species high antiviral and novel activity.