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

Respiratory syncytial virus (RSV) disease burden is greatest between six weeks and 6 months of life, with young age the most common risk factor among hospitalised 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 one year revealed diminished expression of interferon epsilon (IFNE), a poorly characterised type I IFN, in newborns versus one-year. We hypothesised, therefore, that IFNE plays an important role during infant RSV infection. We found that IFNE is endogenously expressed in airway epithelial cell lines. Recombinant human IFN{varepsilon} (rhIFN{varepsilon}) 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 rhIFN{varepsilon} was diminished relative to rhIFN beta (rhIFN{beta}1) or rhIFN lambda-1 (rhIFN{lambda}1), as evidenced by IC50 data. Importantly, rhIFN{varepsilon} induced similar ISGs as rhIFN{beta}1 but demonstrated a transient temporal expression profile that differed from both rhIFN{beta}1 and rhIFN{lambda}1. These results suggest that lower IFN{varepsilon} expression at birth may contribute to increased susceptibility to severe RSV-associated disease, offering insights into potential therapeutic interventions.