Virology group, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.
Nat Commun. 2022 Jul 13;13(1):4054. 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.
建立引发大流行的人畜共患病毒，如西班牙流感和新冠病毒，需要适应人类受体。跨越禽-人物种屏障的甲型流感病毒（IAV）从结合禽型α2-3 连接的唾液酸（2-3Sia）转变为结合人型 2-6Sia 受体。在这里，我们表明这种特异性转变并不像通常假设的那样是二分的。使用混合合成聚糖梯度 2-3Sia 和 2-6Sia 比较结合和进入特异性，并通过在无唾液酸细胞系表面和从这些细胞分泌的唾液糖蛋白上使用遗传改造的 Sia 库来实现。表达一系列（混合）2-3Sia 和 2-6Sia 密度表明，非结合的人型受体可有效增强禽 IAV 的结合和进入，前提是存在低密度的高亲和力禽型受体，反之亦然。考虑到体内遇到的唾液糖受体的异质性，异多价结合在生理上是相关的，并将影响导致宿主适应的进化途径。
