Cross-Species Genome-Wide Analysis Reveals Molecular and Functional Diversity of the Unconventional Interferon-? Subtype

Shields, Lauren E.; Jennings, Jordan; Liu, Qinfang; Lee, Jinhwa; Ma, Wenjun; Blecha, Frank; Miller, Laura C.; Sang, Yongming

In the canonical IFN signaling, IFNs engage type-specific IFN receptors (such as IFNAR1/2 or IFNLR1/IL10RB for type I or III IFNs, respectively) on the cytoplasmic membrane to induce expression of hundreds of ISGs that play roles in restricting viruses and regulating other biological responses (4, 38) . To compare the efficacy of IFN-ω in induction of ISGs with IFN-α/β, we detected the expression of six ISGs representing both robust antiviral genes and tunable immunomodulatory genes across porcine, human, monkey and mouse cells (35, 41) . Porcine IFNω subtype, particularly IFN-ω5, generally showed higher activity in induction of some robust genes and most tunable genes, as well as being broader efficacy in human, monkey, and mouse cells. We hypothesize that this differential activity in induction of ISGs contributes to the superior antiviral activity of the IFN-ω5 peptide; however, which ISGs play a critical role will require future mechanistic studies using the knock-out/-in models (35, 41) . In contrast to the pro-inflammatory role of IFN-γ in immune regulation, recent studies demonstrated primary antiinflammatory activity as well as immune-homeostatic regulation of innate immune IFNs (3, 4) . In this regard, we and others have shown that unconventional IFNs, such as porcine IFN-ω and -δ subtypes, may have evolved to be subject for anti-inflammatory regulation during antiviral response, particularly for those IFN subtypes that show constitutive and epithelial expression (1-7) .