Primary nasal viral infection rewires tissue-scale memory response dynamics 3043

Description The nasal mucosa is often a major 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 mouse nasal mucosa, sampling three regions during primary influenza (IAV) infection and rechallenge. Compositional analysis showed restricted infection to respiratory mucosa with coordinated stepwise changes in innate and adaptive immune and epithelial cell subsets and states occurring 2-14 days post infection. We identify and characterize a rare subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells, which concurrently increase with tissue-resident memory T (TRM)-like cells and exist in human nasal mid-turbinate. Proportionality analysis, cell-cell communication inference, microscopy, and flow cytometry underscored the CXCL16–CXCR6 axis between KNIIFE and TRM cells. Secondary IAV challenge with matched and unmatched IAV strains induced accelerated and coordinated myeloid and lymphoid responses without epithelial proliferation, that was amplified without neutralizing antibodies. These results mimic conserved responses measured in serial human nasal swabs collected during breakthrough SARS-CoV-2 infection. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses. Funding Sources Supported by a CRI Irvington Postdoc. Fellowship; AbbVie-HMS Alliance Program; NY Stem Cell Fndn.; NIH R01 HL162642; NIH R01 DE031928; Pew Charitable Trusts Biomed. Scholars; CZI Pediatric Networks; Broad Next Gen. Award. Topic Categories Mucosal and Regional Immunology (MUC)