Abstract
Human H3N2 influenza viruses, introduced during the 1968 pandemic, have evolved to recognize human-type sialic acid-containing receptors (Neu5Acα2-6Gal) extended with at least three LacNAc (Galβ1-4GlcNAc) repeats. To investigate this restriction in the context of virus attachment to the airway epithelium, we comprehensively analyzed the glycome of human nasal and tracheal epithelial cells. Using a synthetic N-glycan library that reflects the structural diversity of the human airway glycome, we found that only bi-antennary N-glycans with extended human-type receptors on at least one branch serve as receptors for the recent H3 hemagglutinins (HAs). Such receptors are found on tracheal epithelium but are deficient in nasal epithelium. Immunofluorescence analysis on human trachea reveals that recent H3 HAs preferentially attach to ciliated cells, consistent with single-cell RNA sequencing analysis indicating that these cells express glycosyltransferases that produce extended glycan chains. These findings suggest that H3N2 viruses have developed a tropism for tracheal ciliated cells.
Competing Interest Statement
The authors have declared no competing interest.
Funder Information Declared
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, AI 114730, Contract No. 75N93021C00015
The Wellcome Trust, Grant 082098
Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.09.12.675939v1
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