Getty, E. | bioRxiv Science

bioRxiv2026

A host ATPase essential for rhinovirus replication is an antiviral target with a high barrier to resistance

Rhinoviruses are the leading cause of acute respiratory illnesses and comprise more than 170 types that constantly circulate in humans worldwide. Beyond common colds, rhinoviruses can trigger severe symptoms, particularly in young children, older adults and people with asthma or chronic obstructive pulmonary disease. Despite their clinical and socio-economic impact, no approved vaccine or antiviral treatment exist. Here, we uncovered the interaction of the host AAA+ ATPase RUVBL1/2 with rhinovirus non-structural protein 2C and we demonstrated that RUVBL1/2 is strictly and specifically required for the replication of the viral RNA of the most prevalent and pathogenic rhinovirus species. Pharmacological inhibition of RUVBL1/2 ATPase activity efficiently inhibited rhinovirus replication in a human nasal epithelium model, even post-infection. Moreover, serial viral passaging in the presence of a RUVBL1/2 inhibitor did not lead to the emergence of resistance. These findings reveal an unexpected and strong host dependency with promising potential for antiviral targeting.

microbiology↗

bioRxiv2025

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.

microbiology↗