Primary nasal viral infection rewires the tissue-scale memory response

Author:

Kazer Samuel W.ORCID,Match Colette Matysiak,Langan Erica M.,LaSalle Thomas J.,Marbourg Jessica,Naughton Katherine,O’Leary Elise,von Andrian Ulrich H.,Ordovas-Montanes Jose

Abstract

ABSTRACTThe nasal mucosa is frequently the initial site of respiratory viral infection, replication, and transmission. Recent work has started to clarify the independent responses of epithelial, myeloid, and lymphoid cells to viral infection in the nasal mucosa, but their spatiotemporal coordination and relative importance remain unclear. Furthermore, understanding whether and how primary infection shapes tissue-scale memory responses to secondary challenge is critical for the rational design of nasal-targeting therapeutics and vaccines. Here, we generated a single-cell RNA-sequencing (scRNA-seq) atlas of the murine nasal mucosa sampling three distinct regions before and during primary and secondary influenza infection. Primary infection was largely restricted to respiratory mucosa and induced stepwise changes in cell type, subset, and state composition over time. Interferon (IFN)-responsive neutrophils appeared 2 days post infection (dpi) and preceded transient IFN-responsive/cycling epithelial cell responses 5 dpi, which coincided with broader antiviral monocyte and NK cell accumulation. By 8 dpi, monocyte-derived macrophages expressingCxcl9andCxcl16arose alongside effector cytotoxic CD8 andIfng-expressing CD4 T cells. Following viral clearance (14 dpi), rare, previously undescribedMeg3+MHC-II+ epithelial cells andKrt13+nasalimmune-interactingfloorepithelial (KNIIFE) cells expressing multiple genes with immune communication potential increased concurrently with tissue-resident memory T (TRM)-like cells and IgG+/IgA+ plasma cells. Proportionality analysis coupled with cell-cell communication inference underscored the CXCL16–CXCR6 signaling axis in effector CD8 T cell and TRMcell formation in the nasal mucosa. Secondary influenza challenge administered 60 dpi induced an accelerated and coordinated myeloid and lymphoid response with reduced IFN-responsive epithelial activity, illustrating how tissue-scale memory to natural infection engages both myeloid and lymphoid cells without broad epithelial inflammation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses upon rechallenge.

Publisher

Cold Spring Harbor Laboratory

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