Limited nasal IFN production contributes to delayed respiratory virus clearance and suboptimal vaccine responses.

Acute lower respiratory infections are the primary cause of global mortality in postneonatal children. Most respiratory viruses primarily involve upper airway infection and inflammation, yet nasal responses are poorly characterized. Using a mouse model of human metapneumovirus (HMPV), we found viral burden was higher in nasal airways and exhibited delayed clearance. Despite high burden, there was low nasal expression of type I and III interferon (IFN). Single-cell RNA-sequencing (scRNA-Seq) from HMPV-infected mice showed lower nasal IFN-stimulated gene (ISG) expression and nasal enrichment of genes negatively regulating IFN. scRNA-Seq of patients with COVID-19 verified lower ISG expression in upper airways. HMPV infection downregulated nasal expression of IFN regulatory factor 3, suggesting a mechanism for limited response. To rescue the quiescent environment, we administered type I or III IFN to upper airways early postinfection, leading to lower nasal HMPV titer and virus-specific CD8+ T cell upregulation. Intranasal immunization adjuvanted with type I or III IFN improved immune response, reduced clinical disease, and enhanced viral clearance in HMPV and influenza infection. IFN adjuvant increased recruitment of dendritic cells, recruitment of resident memory T cells, and neutralizing antibodies. These findings reveal locally suppressed IFN production contributes to a quiescent nasal immune landscape that delays viral clearance and impairs mucosal vaccine responses.