Ríos Carrasco María, Lin Ting-Hui, Zhu Xueyong, García Alba Gabarroca, Uslu Elif, Liang Ruonan, Spruit Cindy M, Richard Mathilde, Boons Geert-Jan, Wilson Ian A, de Vries Robert P
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584CG, Utrecht, The Netherlands.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
bioRxiv. 2025 Jan 10:2025.01.10.632119. doi: 10.1101/2025.01.10.632119.
H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naïve to H5 viruses. A significant determinant of transmission to and between humans is the ability of the influenza A virus hemagglutinin (HA) protein to shift from an avian-type to a human-type receptor specificity. Here, we demonstrate that a 2016 2.3.4.4e virus HA can convert to human-type receptor binding via a single Q226L mutation, in contrast to a cleavage-modified 2016 2.3.4.4b virus HA. Using glycan arrays, x-ray structural analyses, tissue- and direct glycan binding, we show that L133aΔ and 227Q are vital for this phenotype. Thus, whereas the 2.3.4.4e virus HA only needs a single amino acid mutation, the modified 2.3.4.4b HA was not easily converted to human-type receptor specificity.
H5Nx病毒继续在全球范围内对禽类和哺乳动物造成严重破坏。该病毒的特点是能够在高滴度下复制，并在各种气候环境中的多种宿主中高效传播。幸运的是，人传人情况很少见。然而，如果发生这种情况，可能会引发大流行，因为人类对H5病毒在免疫上缺乏抵抗力。人传人及人际传播的一个重要决定因素是甲型流感病毒血凝素（HA）蛋白从禽型受体特异性转变为人类型受体特异性的能力。在这里，我们证明，与经过裂解修饰的2016 2.3.4.4b病毒HA不同，2016 2.3.4.4e病毒HA通过单个Q226L突变可转变为人类型受体结合。通过聚糖阵列、X射线结构分析、组织和直接聚糖结合，我们表明L133aΔ和227Q对这种表型至关重要。因此，虽然2.3.4.4e病毒HA只需要单个氨基酸突变，但经过修饰的2.3.4.4b HA不容易转变为人类型受体特异性。
