Interferon ε restricts Zika virus infection in the female reproductive tract

Author:

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

Abstract

AbstractInterferon ε (IFNε) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections (STIs). 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 infectionin vivois unknown. Here, 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 certain immune and other cells at baseline or after exposure to viruses or specific 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 protectedIfnε-/-mice and highly susceptibleIfnar1-/-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 transmission of ZIKV in the context of sexual contact.SignificanceInterferon ε (IFNε), a unique Type I IFN that is highly expressed in the epithelium of the female reproductive tract (FRT), is thought to protect the host against sexually transmitted infections (STIs) but the mechanism of action is not defined. Zika virus (ZIKV), a causative agent for preterm birth and other severe diseases in pregnant women, can be spread through vaginal transmission. Here, we show that mice lacking theIfnεgene have abnormal epithelial development and tissue architecture in the cervicovaginal tract. The role of IFNε in protecting host against ZIKV is FRT-specific and is independent of IFNAR1 signaling. Our findings suggest potential preventive strategies based on harnessing mucosal immunity against STIs.

Publisher

Cold Spring Harbor Laboratory

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1. Interferon Epsilon: Properties and Functions;Current Molecular Medicine;2024-06-07

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