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Cited by 17Influenza Virus Research StudiesGlycosylation and Glycoproteins ResearchCarbohydrate Chemistry and Synthesis

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Epistasis in the receptor-binding domain of contemporary H3N2 viruses that reverted to bind sialylated di-LacNAc repeats

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Liang, Ruonan, Peccati, Francesca, Ponse, Niels L.D., Uslu, Elif, de Rooij, Annelies J.H., Han, Alvin X., Boons, Geert-Jan, Unione, Luca, de Vries, Robert P.·2025·Cell Reports
DOI 10.1016/j.celrep.2025.116007PMC PMC12439434

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Abstract

Since the introduction of H3N2 influenza A viruses in the human population, these viruses have continuously evolved to escape human immunity, with mutations occurring in and around the receptor binding site. This process, called antigenic drift, recently resulted in viruses that recognize elongated glycans that are not abundantly displayed in the human respiratory tract. Such receptor specificities hampered our ability to pick and propagate vaccine strains. Using ELISA, glycan array, tissue staining, flow cytometry, and hemagglutinin assays, this study revealed that the most recent H3N2 viruses have expanded receptor specificity by regaining effective recognition to shorter glycans. In recent H3 strains, Y159 and T160 are responsible for restricted binding to elongated glycans; in contemporary strains, however, Y159N and T160I dominate with a consequent loss of strength in receptor binding. Yet, effective receptor interaction is rescued by a remote mutation in the 190-helix, Y195F. The results demonstrate epistasis of critical residues in three of the four structural elements composing the HA receptor-binding site (the 130-loop, 150-loop, and 190-helix), which synergistically contribute to shape receptor binding specificity. Interestingly, a positive correlation exists between binding to an asymmetrical N-glycan containing an α2,6 sialylated tri-LacNAc arm and binding to human and ferret respiratory tract tissues. Together, these results elucidate the epistatic nature of receptor binding specificity during influenza A virus H3N2 evolution.

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Metadata

Authors
Liang, R., Peccati, F., Ponse, N. L. D., Uslu, E., de Rooij, A. J. H., Han, A. X., Boons, G.-J., Unione, L., & de Vries, R. P.
Affiliations
  • Utrecht University (NL)
  • Ikerbasque (ES)
  • Amsterdam University Medical Centers (NL)
  • University of Georgia (US)
Corresponding author
de Vries, Robert P.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2025-08
Volume
44
Issue
8
Pages
116007
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2025.116007
PMC
PMC12439434
OpenAlex
W4412493743
Cited by
17
References
2
Citations by year
2026: 13 · 2025: 4
FWCI
11.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • HORIZON EUROPE European Research Council (101117639-Glyco13Cell)
  • National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases (R01 AI165692)
  • Agencia Estatal de Investigación (EUR2023-14346, RYC2022-036457-I)
  • China Sponsorship Council
  • China Scholarship Council (202209120001)
  • European Research Council (ERC-2023-STG)
  • Ministerio de Ciencia e Innovación
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
Keywords
H3N2, epistasis, antigenic drift, receptor specificity

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