Interferon ε restricts Zika virus infection in the female reproductive tract

Chuan Xu, Annie Wang, Laith Ebraham, Liam Sullivan, Carley Tasker, Vanessa Pizutelli, Jennifer Couret, Cyril Hernandez, Priyanka Kolli, Pratik Q. Deb, Luke Fritzky, Selvakumar Subbian, Nan Gao, Yungtai Lo, Mirella Salvatore, Amariliz Rivera, Alexander Lemenze, Patricia Fitzgerald-Bocarsly, Sanjay Tyagi, Wuyuan LuAimee Beaulieu, Theresa L. Chang

Research output: Contribution to journalArticlepeer-review


Interferon ε (IFNε) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections. Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFNε contributes to protection against ZIKV infection in vivo is unknown. In this study, we show that IFNε plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFNε was expressed not only by epithelial cells in the FRT but also by immune and stromal cells at baseline or after exposure to viruses or specific Toll-like receptor (TLR) agonists. IFNε-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal but not subcutaneous ZIKV infection. IFNε deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFNε protected Ifnε−/− mice and highly susceptible Ifnar1−/− mice against vaginal ZIKV infection, indicating that IFNε was sufficient to provide protection even in the absence of signals from other type I IFNs and in an IFNAR1-independent manner. Our findings reveal a potentially critical role for IFNε in mediating protection against the transmission of ZIKV in the context of sexual contact.

Original languageEnglish
Article numberpgad350
JournalPNAS Nexus
Issue number11
StatePublished - 1 Nov 2023
Externally publishedYes


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