A distinct signature of interferon-stimulated genes linked to cross-protection against secondary viral infections in primary bronchial epithelial cells

Respiratory viral infections, such as those caused by rhinovirus, adenovirus, influenza, respiratory syncytial virus (RSV), and SARS-CoV-2, represent a major global health challenge. Despite extensive research, effective and specific antiviral treatments for these infections are still lacking, with patient care often limited to symptomatic relief. The SARS-CoV-2 pandemic, alongside the emergence of avian flu H1N1 and Nipah virus, has underscored the critical role of the respiratory tract as a critical viral target. Respiratory viral infections exhibit marked variability in infectivity and disease severity across different age groups. Epidemiological and cell-based evidence highlights distinct impacts on pediatric and adult populations. For instance, the COVID-19 disproportionately affected the elderly, while viruses like rhinovirus and adenovirus often cause severe morbidity in children. Additionally, clinical studies indicate that a primary respiratory infection can provide transient protection against subsequent infections by the same or different respiratory viruses. In this study, we utilized a differentiated bronchial epithelial (BE) model derived from pediatric and adult donors to assess age-dependent differences under resting conditions and during viral infections. We investigated how donor age influences infection susceptibility and viral spread within the BE, focusing on the transcriptional response to rhinovirus types A and C, and adenovirus type 5. Importantly, we demonstrate that prior viral infection confers protection against subsequent infections, regardless of donor age or the initial virus type. This cross-protection is driven by interferon signaling, leading to the expression of a narrow and specific set of interferon-stimulated genes (ISGs) in both infected and bystander cells. Notably, IFI44L shows the strongest correlation with the level of cross protection and that its overexpression alone significantly reduces viral infection of BE. These findings suggest a distinctive, interferon-driven innate immune response profile in the BE, offering critical insights for the development of new therapeutic strategies against respiratory viral infections.