Primary nasal influenza infection rewires tissue-scale memory response dynamics

The nasal mucosa is often the initial site of respiratory viral infection, replication, and transmission. Understanding how infection shapes tissue-scale primary and memory responses is critical for designing mucosal therapeutics and vaccines. We generated a single-cell RNA-sequencing atlas of the murine nasal mucosa, sampling three regions during primary influenza infection and rechallenge. Compositional analysis revealed restricted infection to the respiratory mucosa with stepwise changes in immune and epithelial cell subsets and states. We identified and characterized a rare subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells, which concurrently increased with tissue-resident memory T (TRM)-like cells. Proportionality analysis, cell-cell communication inference, and microscopy underscored the CXCL16-CXCR6 axis between KNIIFE and TRM cells. Secondary influenza challenge induced accelerated and coordinated myeloid and lymphoid responses without epithelial proliferation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses. [Display omitted] •Influenza infection induces stepwise changes in nasal epithelial and immune subsets•Single-cell compositional analyses reveal coordinated changes in time and space•Cxcl16+ epithelial KNIIFE cells line the nasal floor near Cxcr6+ TRM cells•Nasal viral rechallenge induces rapid and concerted myeloid and T cell responses The nasal mucosa is a key barrier for respiratory infections, but the cellular responses therein are poorly understood. Kazer et al. generate a longitudinal tissue-scale single-cell nasal atlas during IAV infection and rechallenge, identifying unique epithelial subsets responding to infection and revealing highly coordinated myeloid and T cell responses during rechallenge.