Human-type sialic acid receptors contribute to avian influenza A virus binding and entry by hetero-multivalent interactions

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Establishment of zoonotic viruses, causing pandemics like the Spanish flu and Covid-19, requires adaptation to human receptors. Pandemic influenza A viruses (IAV) that crossed the avian-human species barrier switched from binding avian-type α2-3-linked sialic acid (2-3Sia) to human-type 2-6Sia receptors. Here, we show that this specificity switch is however less dichotomous as generally assumed. Binding and entry specificity were compared using mixed synthetic glycan gradients of 2-3Sia and 2-6Sia and by employing a genetically remodeled Sia repertoire on the surface of a Sia-free cell line and on a sialoglycoprotein secreted from these cells. Expression of a range of (mixed) 2-3Sia and 2-6Sia densities shows that non-binding human-type receptors efficiently enhanced avian IAV binding and entry provided the presence of a low density of high affinity avian-type receptors, and vice versa. Considering the heterogeneity of sialoglycan receptors encountered in vivo, hetero-multivalent binding is physiologically relevant and will impact evolutionary pathways leading to host adaptation.

Original languageEnglish
Article number4054
JournalNature Communications
Volume13
ISSN2041-1723
DOIs
Publication statusPublished - 2022

Bibliographical note

© 2022. The Author(s).

    Research areas

  • Animals, COVID-19, Hemagglutinin Glycoproteins, Influenza Virus/metabolism, Humans, Influenza A virus/metabolism, Influenza Pandemic, 1918-1919, Influenza, Human, N-Acetylneuraminic Acid/metabolism, Receptors, Cell Surface/genetics, Receptors, Virus/metabolism

ID: 322119364