Glycan remodeled erythrocytes facilitate antigenic characterization of recent A/H3N2 influenza viruses

Frederik Broszeit, Rosanne J. van Beek, Luca Unione, Theo M. Bestebroer, Digantkumar Chapla, Jeong Yeh Yang, Kelley W. Moremen, Sander Herfst, Ron A.M. Fouchier, Robert P. de Vries*, Geert Jan Boons

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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During circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities. These viruses lost the ability to agglutinate erythrocytes critical for antigenic characterization and give low yields and acquire adaptive mutations when cultured in eggs and cells, contributing to recent vaccine challenges. Examination of receptor specificities of A/H3N2 viruses reveals that recent viruses compensated for decreased binding of the prototypic human receptor by recognizing α2,6-sialosides on extended LacNAc moieties. Erythrocyte glycomics shows an absence of extended glycans providing a rationale for lack of agglutination by recent A/H3N2 viruses. A glycan remodeling approach installing functional receptors on erythrocytes, allows antigenic characterization of recent A/H3N2 viruses confirming the cocirculation of antigenically different viruses in humans. Computational analysis of HAs in complex with sialosides having extended LacNAc moieties reveals that mutations distal to the RBD reoriented the Y159 side chain resulting in an extended receptor binding site.

Original languageEnglish
Article number5449
Number of pages12
JournalNature Communications
Issue number1
Publication statusPublished - 14 Sept 2021

Bibliographical note

Funding Information:
This project is supported by the Netherlands Organization for Scientific Research (NWO TOPPUNT 718.015.003) to G.-J.B., R.P.dV. is a recipient of ERC starting grant 802780 and a Beijerinck Premium of the Royal Dutch Academy of Sciences. S.H. is supported by NWO VIDI grant 91715372, R.A.F. by NIAID/NIH contract HHSN272201400008C, and K.W.M and G.-J.B. by U.S. National Institutes of Health grants (R01GM130915, P41GM103390, and U01GM120408). We thank T. Manders, dr. H.G.R. Matthijs and dr. R.M. Dwars (Faculty of Veterinary Sciences, Utrecht University) for providing chicken blood and M. Pronk and R. van Beek (Department of Viroscience, Erasmus MC) for technical assistance. Dr. L. Liu (CCRC) and dr. M.A. Wolfert (Utrecht University) developed, printed, and validated the glycan microarray. We would like to thank Dirk Eggink from the Amsterdam Medical Center for supplying the CR8020 antibody.

Publisher Copyright:
© 2021, The Author(s).


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