Chemoenzymatic Synthesis of N-Linked Glycan Receptors of H1N1 Influenza Virus on Human Airway Epithelial Cells

Attachment of human influenza virus to the surface of airway epithelial cells is mediated by the hemagglutinin (HA) that binds to Neu5Acα2-6Gal-terminated glycans termed human-type receptors. Numerous reports suggest that current H1N1 and H3N2 influenza viruses that annually infect humans have evolved to preferentially recognize only a subset of human-type receptors. Based on glycomics analysis of nasal and tracheal human epithelial cells, we have defined and chemoenzymatically synthesized a novel library of α2-6 sialylated N-linked glycans that represent the diversity of structures that are candidate receptors of human influenza viruses. Using this library, we investigated the specificity of the HAs of H1N1 viruses stemming from two pandemics in 1918 and 2009. We find that H1N1 viruses from both pandemics have maintained a remarkably similar receptor specificity, with a strong preference for α2-6 sialylated biantennary N-linked glycans extended with two or more Galβ1-4GlcNAc (LacNAc) repeats on at least one antenna.