Interferon e restricts Zika infection at the female reproductive tract

Interferon e (IFNe), a unique type I IFN, is thought to protect the host against sexually transmitted infections. Unlike conventional type I IFNs (e.g., IFNa/ß), whose expression is undetectable at baseline, IFNe expression is detectable in the epithelium of mucosal tissues, particularly the female reproductive tract (FRT). We found that IFNe expression was not limited to epithelial cells at the FRT. Importantly, in contrast to previous reports, IFNe expression in plasmacytoid dendritic cells and primary cervical epithelial cells was induced by viral infection and by activation of TLR3 or 4 in PBMCs. Induction of IFNe mRNAs was also found in cervicovaginal tissues (CVT) of Zika virus (ZIKV)-infected mice. Mice with IFNe deficiency (Ifne-/-) did not have impaired induction of interferon-stimulated genes except IFNl, but had altered epithelial and collagen structure in the CVT. Ifne-/- mice exhibited increased susceptibility to ZIKV infection via an intravaginal route but not via a subcutaneous route, indicating that the protective effect of IFNe was specific to the FRT. Infected Ifne-/- mice had higher and more sustained viral loads than infected wild-type (WT) mice. Detection of ZIKV infection by single molecule in situ hybridization confirmed that virus spread faster in Ifne-/- mice than in WT mice. Recombinant murine IFNe protected Ifnar1-/- mice against ZIKV infection when administered through an intravaginal route but not when administered through a subcutaneous route, indicating that the specific role of IFNe at the FRT is independent of IFNAR1 signaling. Our findings indicate that IFNe mediates a novel FRT-specific protective effect on mucosal immunity that limits Zika virus spread. Overall design: female C57BL/6J (WT) and IFN epsilon deficiency mice generated by using CRISPR-Cas9 at 6-12 weeks were treated with Depo-Provera for 12 days. Cervicovaginal tissues were harvested and total RNAs were prepared for RNAseq analyses.