Age-dependent expression and antiviral activity of interferon epsilon in respiratory epithelium

Respiratory syncytial virus (RSV) disease burden is greatest between 6 weeks and 6 months of life, with young age the most common risk factor among hospitalized children. A robust innate immune response in the airway epithelium is crucial for mitigating RSV-associated disease, but early-life immune responses to infection remain largely unexplored. RNA-seq analysis of RSV-infected primary nasal epithelial cell cultures from healthy infants at birth and 1 year revealed diminished expression of interferon epsilon (IFNE), a poorly characterized type I IFN, in newborns vs 1 year. We hypothesized, therefore, that IFNE plays an important role during infant RSV infection. We found that IFNE is basally expressed in airway epithelial cell lines. Recombinant human IFNε (rhIFNε) induced an antiviral state against an RSV clinical isolate and related Sendai virus, but not SARS-CoV-2 under the conditions tested. The antiviral potency of rhIFNε was diminished relative to rhIFN beta (rhIFNβ1) or rhIFN lambda-1 (rhIFNλ1), as evidenced by IC₅₀ data. Importantly, rhIFNε induced similar ISGs as rhIFNβ1 but demonstrated a transient temporal expression profile that differed from both rhIFNβ1 and rhIFNλ1. These results suggest that lower IFNε expression at birth may contribute to increased susceptibility to severe RSV-associated disease, offering insights into potential interventions.