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

Expansion of the IFN complex and IFN-ω diversity in bats and ungulates represent signature events of type I IFN evolution (7) (8) (9) (10) (11) (12) (13) (14) (15) . We hypothesize that this subtype-expansion confers functional diversification that is necessary in regulating immune responses against species-specific and even cross-species viral infections (2, (7) (8) (9) (10) (11) (12) (13) (14) (15) . Focusing on the IFN-ω members and their antiviral and inflammatory regulation, we characterized family-wide porcine innate immune IFNs for their functional spectrum and therapeutic potential (9, 10, 13, 14) , which was profiled against two RNA viruses: porcine reproductive and respiratory syndrome virus (PRRSV), and influenza A virus. Both viruses have a high impact on the swine industry and influenza A virus in swine, also threatens public health (13, 16) . Here, we show that vertebrate IFN-ω subtype has evolved several novel features, which include: (1) being a signature multi-gene subtype expanding particularly in bats and ungulates (7, 9, 17, 18) , (2) emerging isoforms that have much higher antiviral potency than typical IFN-α (14, 18, 19) , (3) highly crossspecies antiviral (but little anti-proliferative) activity exerted in cells of humans and other mammalian species (20) , and (4) other potential novel molecular and functional properties (3, 4, 18, 20) . These observations suggest that animal unconventional IFN subtypes have diversified their molecular composition to extend functional spectrum particularly in antiviral and immunomodulatory regulation (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) .