Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection

Abstract

The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNϵ) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs α, β and λ. We show the necessity of IFNϵ for Zika Virus (ZIKV) protection by: increased susceptibility of IFNϵ-/- mice; their "rescue" by intravaginal recombinant IFNϵ treatment and blockade of protective endogenous IFNϵ by neutralising antibody. Complementary studies in human FRT cell lines showed IFNϵ had potent anti-ZIKV activity, associated with transcriptome responses similar to IFNλ but lacking the proinflammatory gene signature of IFNα. IFNϵ activated STAT1/2 pathways similar to IFNα and λ that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFNϵ exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFNϵ. However, the IFNϵ expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFNβ or λ. Thus, the constitutive expression of IFNϵ provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFNϵ provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy.