Hierarchical Multivalent Effects Control Influenza Host Specificity,ACS Central Science

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Hierarchical Multivalent Effects Control Influenza Host Specificity
ACS Central Science ( IF 12.7 ) Pub Date : 2020-11-12 , DOI: 10.1021/acscentsci.0c01175
Nico J. Overeem ₁ , P. H. Erik Hamming ₁ , Oliver C. Grant ₂ , Daniele Di Iorio ₁ , Malte Tieke ₃ , M. Candelaria Bertolino ₁ , Zeshi Li ₄ , Gaël Vos ₄ , Robert P. de Vries ₄ , Robert J. Woods ₂ , Nicholas B. Tito ₅ , Geert-Jan P. H. Boons _{2,

4,

6,

7} , Erhard van der Vries _{3,

8,

9} , Jurriaan Huskens ₁

Affiliation

Molecular Nanofabrication Group, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States
Division of Virology, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
Electric Ant Lab, Science Park 106, 1098 XG Amsterdam, The Netherlands
Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands
Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
Royal GD, Arnsbergstraat 7, 7418 EZ Deventer, The Netherlands
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands

Understanding how emerging influenza viruses recognize host cells is critical in evaluating their zoonotic potential, pathogenicity, and transmissibility between humans. The surface of the influenza virus is covered with hemagglutinin (HA) proteins that can form multiple interactions with sialic acid-terminated glycans on the host cell surface. This multivalent binding affects the selectivity of the virus in ways that cannot be predicted from the individual receptor–ligand interactions alone. Here, we show that the intrinsic structural and energetic differences between the interactions of avian- or human-type receptors with influenza HA translate from individual site affinity and orientation through receptor length and density on the surface into virus avidity and specificity. We introduce a method to measure virus avidity using receptor density gradients. We found that influenza viruses attached stably to a surface at receptor densities that correspond to a minimum number of approximately 8 HA–glycan interactions, but more interactions were required if the receptors were short and human-type. Thus, the avidity and specificity of influenza viruses for a host cell depend not on the sialic acid linkage alone but on a combination of linkage and the length and density of receptors on the cell surface. Our findings suggest that threshold receptor densities play a key role in virus tropism, which is a predicting factor for both their virulence and zoonotic potential.

中文翻译：

多层多价效应控制流感宿主特异性

了解新兴的流感病毒如何识别宿主细胞对于评估其人畜共患病潜力，致病性和人与人之间的传播能力至关重要。流感病毒的表面覆盖有血凝素（HA）蛋白，可与宿主细胞表面上以唾液酸封端的聚糖形成多种相互作用。这种多价结合以单独的受体-配体相互作用无法预测的方式影响病毒的选择性。在这里，我们显示禽流感或人类流感病毒与人类受体之间相互作用的内在结构和能量差异，从单个位点的亲和力和方向，通过表面上受体的长度和密度转化为病毒的亲和力和特异性。我们介绍一种使用受体密度梯度来测量病毒亲和力的方法。我们发现流感病毒以对应至少约8个HA-聚糖相互作用的最小数目的受体密度稳定附着在表面上，但是如果受体短且为人型，则需要更多的相互作用。因此，流感病毒对宿主细胞的亲和力和特异性不仅仅取决于唾液酸键，还取决于键的结合以及细胞表面上受体的长度和密度。我们的研究结果表明，阈值受体密度在病毒嗜性中起关键作用，这是它们的毒力和人畜共患病潜力的预测因素。我们发现流感病毒以对应至少约8个HA-聚糖相互作用的最小数目的受体密度稳定附着在表面上，但是如果受体短而为人型，则需要更多的相互作用。因此，流感病毒对宿主细胞的亲和力和特异性不仅仅取决于唾液酸键，还取决于键的结合以及细胞表面上受体的长度和密度。我们的研究结果表明，阈值受体密度在病毒嗜性中起关键作用，这是它们的毒力和人畜共患病潜力的预测因素。我们发现流感病毒以对应至少约8个HA-聚糖相互作用的最小数目的受体密度稳定附着在表面上，但是如果受体短且为人型，则需要更多的相互作用。因此，流感病毒对宿主细胞的亲和力和特异性不仅仅取决于唾液酸键，还取决于键的结合以及细胞表面上受体的长度和密度。我们的研究结果表明，阈值受体密度在病毒嗜性中起关键作用，这是它们的毒力和人畜共患病潜力的预测因素。流感病毒对宿主细胞的亲和力和特异性不仅仅取决于唾液酸键，还取决于键和细胞表面受体长度和密度的组合。我们的研究结果表明，阈值受体密度在病毒嗜性中起关键作用，这是它们的毒力和人畜共患病潜力的预测因素。流感病毒对宿主细胞的亲和力和特异性不仅仅取决于唾液酸键，还取决于键的结合以及细胞表面受体的长度和密度。我们的研究结果表明，阈值受体密度在病毒嗜性中起关键作用，这是它们的毒力和人畜共患病潜力的预测因素。

更新日期：2020-12-23

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