Abstract: The mucociliary apparatus of the airway epithelium serves as a critical defense system, orchestrating the secretion of mucins and other proteins to entrap and neutralize pathogens. Secretory cells within this barrier exhibit a high degree of molecular and functional heterogeneity, facilitating dynamic responses to environmental challenges. Recent scRNA-seq studies have elucidated the transcriptional heterogeneity of secretory cells, yet their lack of spatial context limits understanding of localized functionality. Here, we leveraged Stereo-seq to generate a high-resolution map of human tracheal biopsies, capturing the spatial transcriptomic landscape of the surface epithelium and submucosal glands. Our analysis revealed discrete regional expression patterns of secretory protein families, including MUC5AC and MUC5B mucins, SCGB3A1 secretoglobins, and serous proteins such as PRH and PRB family. These spatially resolved profiles suggest functional compartmentalization critical for mucosal homeostasis and pathogen clearance. The spatial data also revealed a coordinated immune network, with IgG- and IgA-producing plasma cells preferentially localized near submucosal glands. Furthermore, ex vivo infection experiments using influenza virus revealed region-specific transcriptional responses, providing mechanistic insights into spatially resolved host-pathogen dynamics.
