Interferon Epsilon Protects Epithelial Barriers from Viral Infection through Autocrine Intracellular Signaling

Abstract

Antiviral defenses at mucosal barriers are essential for preventing viral entry and systemic infection. Interferon epsilon (IFN{varepsilon}) is a unique type I IFN that, unlike other family members, is not induced by infection but is constitutively expressed in epithelial tissues. IFN{varepsilon} was initially characterized in the female reproductive tract (FRT), where it provides broad antiviral protection, but its roles outside the FRT remain poorly defined. Here, we used Ifn{varepsilon}-/- mice and single-cell RNA sequencing to delineate IFN{varepsilon} function across distinct mucosal surfaces. In the FRT, Ifn{varepsilon} expression was restricted to specific epithelial subsets, was independent of estrous stage, and maintained basal ISG expression. IFN{varepsilon} was also retained intracellularly in primary human FRT-derived cells. Extending these analyses to the intestine, we found that IFN{varepsilon} is highly expressed in villous-tip enterocytes of the small intestine in vivo, where it sustains inflammatory enterocyte subsets and maintains type III IFN expression. Loss of Ifn{varepsilon} depleted these subsets and rendered mice more susceptible to enteric viral infection. Together, these findings establish IFN{varepsilon} as a constitutively expressed, spatially restricted IFN that coordinates mucosal antiviral defenses across both reproductive and gastrointestinal epithelial tissues.