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

作者：Mengying Liu, Liane Z. X. Huang, Anthony A. Smits, Christian Büll, Yoshiki Narimatsu, Frank J. M. van Kuppeveld, Henrik Clausen, Cornelis A. M. de Haan, Erik de Vries · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-31840-0 · 被引用次数：83 · 研究领域：Influenza Virus Research Studies、RNA and protein synthesis mechanisms、Immune Response and Inflammation

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.