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

Author summaryThe female reproductive tract (FRT) is vulnerable to sexually transmitted infections and therefore a well-tuned immune surveillance system is crucial for maintaining a healthy FRT. However, our understanding of the factors that impact viral infection of the FRT and the host response are not well understood. In this work we investigate the role of a hormonally regulated type I interferon, IFN epsilon (IFN epsilon) in control of Zika virus (ZIKV) infection of the FRT. IFN epsilon is unique compared to other canonical type-I IFNs in that it is constitutively expressed by epithelial cells of the FRT with expression levels controlled by progesterone and not in response to viral infection. We demonstrate that IFN epsilon has anti-ZIKV properties using a combination of IFN epsilon KO mice, blockade of endogenous IFN epsilon by neutralising Abs and rescue of IFN epsilon KO mice by recombinant IFN epsilon administered directly to the FRT. Furthermore, we complemented our in vivo studies using human FRT derived cell lines. Importantly, ZIKV NS proteins did not block IFNe expression despite their ability to antagonise the expression of IFN beta or lambda. Collectively this work implicates IFN epsilon as a key type-I IFN that provides a distinct homeostatic antiviral environment in the FRT. The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNe) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs alpha, beta and lambda. We show the necessity of IFNe for Zika Virus (ZIKV) protection by: increased susceptibility of IFNe-/- mice; their rescue by intravaginal recombinant IFNe treatment and blockade of protective endogenous IFNe by neutralising antibody. Complementary studies in human FRT cell lines showed IFNe had potent anti-ZIKV activity, associated with transcriptome responses similar to IFN lambda but lacking the proinflammatory gene signature of IFN alpha. IFNe activated STAT1/2 pathways similar to IFN alpha and lambda that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFN epsilon exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFN epsilon. However, the IFNe expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFN beta or lambda. Thus, the constitutive expression of IFNe 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 IFN epsilon provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy.

Automated summary

This study investigates the role of a hormonally regulated type I interferon, IFN epsilon (IFNε), in controlling Zika virus (ZIKV) infection in the female reproductive tract. The researchers demonstrate that IFNε has anti-ZIKV properties through the use of IFNε KO mice, neutralising antibodies, and recombinant IFNε administered directly to the reproductive tract. Additionally, human cell lines derived from the reproductive tract were used to complement the in vivo studies. This work highlights the importance of IFNε as a key type I interferon in providing an antiviral environment in the female reproductive tract.