The receptor binding properties of H5Nx influenza A viruses have evolved to promiscuously bind to avian-type mucin-like O-glycans

Weber, J.; Ponse, N. L. D.; Zhu, X.; Rios Carrasco, M.; Han, A. X.; Funk, M.; Lin, T.-H.; Gabarroca Garcia, A.; Spruit, C. M.; Yu, W.; Zhang, D.; Wilson, I. A.; Richard, M.; Boons, G.-J.; de Vries, R. P.

doi:10.1101/2025.04.24.650378

bioRxiv · 10.1101/2025.04.24.650378

The receptor binding properties of H5Nx influenza A viruses have evolved to promiscuously bind to avian-type mucin-like O-glycans

Weber, J.·Ponse, N. L. D.·Zhu, X.·Rios Carrasco, M.·Han, A. X.·Funk, M.·Lin, T.-H.·Gabarroca Garcia, A.·Spruit, C. M.·Yu, W.·Zhang, D.·Wilson, I. A.·Richard, M.·Boons, G.-J.·de Vries, R. P.

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Abstract

Highly pathogenic H5Nx influenza A viruses are causing unprecedented, season-independent outbreaks across avian and mammalian species, including dairy cattle, a novel reservoir. The sialoside-binding properties of influenza A hemagglutinin (HA) are strongly related to its ability to infect and transmit between hosts. Mucin-like O-glycans, omnipresent in respiratory tracts, have been understudied as viral receptors due to their complexity. To address this, we synthesized 25 O-linked glycans with diverse sialosides, including modifications by fucosides and sulfates. Our findings reveal that H5Nx 2.3.4.4b viruses uniquely bind core 3 sialyl-Lewisx and Sia-Gal-{beta}3GalNAc, glycans not recognized by classical H5 or other avian viruses. By determining its crystal structure, we resolved the structural features of both structures in an H5 hemagglutinin (HA) from a 2016 2.3.4.4b virus. While these viruses do not bind human-type receptors, their promiscuous receptor specificity enhances binding to human tracheal tissues, suggesting that O-glycan recognition contributes to their zoonotic potential.

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Weber, J., Ponse, N. L. D., Zhu, X., Rios Carrasco, M., Han, A. X., Funk, M., Lin, T.-H., Gabarroca Garcia, A., Spruit, C. M., Yu, W., Zhang, D., Wilson, I. A., Richard, M., Boons, G.-J., de Vries, R. P.. 2025-04-24. The receptor binding properties of H5Nx influenza A viruses have evolved to promiscuously bind to avian-type mucin-like O-glycans. https://doi.org/10.1101/2025.04.24.650378

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