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

• Published in: Nature communications Vol. 13; no. 1; p. 4054
• Main Authors: Liu, Mengying, Huang, Liane Z. X., Smits, Anthony A., Büll, Christian, Narimatsu, Yoshiki, van Kuppeveld, Frank J. M., Clausen, Henrik, de Haan, Cornelis A. M., de Vries, Erik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 38/109; 631/326/596/1578; 631/80/458/1524; 82/80; 82/83; 9/10; Adaptation; Affinity; Avian flu; Binding; COVID-19; Glycan; Glycoproteins; Heterogeneity; Humanities and Social Sciences; Influenza; Influenza A; multidisciplinary; Pandemics; Receptors; Science; Science (multidisciplinary); Sialic acids; Tropism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31840-0

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. It is believed that human Influenza HA glycoprotein attaches to alpha2-6 linked sialic acids (SA) on cells, while avian viruses bind to alpha2-3 linked sialic acids, therewith contributing to host tropism. Here, Liu et al. show that mixing low-affinity alpha2-3 SA with low amounts of high-affinity alpha2-6 SA increases binding and entry of human viruses and the converse for avian virus. This shows that receptor recognition is not as strict as currently assumed and provides evidence that heteromultivalent interactions between human/avian HA and SA contributes to host adaptation.