Hierarchical Multivalent Effects Control Influenza Host Specificity

GRANT, OLIVER C.; BERTOLINO, M. CANDELARIA; DE VRIES, ROBERT P.; BOONS, GEERT-JAN P. H.; HAMMING, P. H. ERIK; TIEKE, MALTE; VOS, GAËL; TITO, NICHOLAS B.; HUSKENS, JURRIAAN; OVEREEM, NICO J.; DI IORIO, DANIELE; LI, ZESHI; WOODS, ROBERT J.; VAN DER VRIES, ERHARD

ACS Central Science

ACS Central Science

Lugar: Washington, D. C.; Año: 2020

2374-7943

Understanding how emerging influenza viruses6 recognize host cells is critical in evaluating their zoonotic potential,7 pathogenicity, and transmissibility between humans. The surface of8 the influenza virus is covered with hemagglutinin (HA) proteins9 that can form multiple interactions with sialic acid-terminated10 glycans on the host cell surface. This multivalent binding affects11 the selectivity of the virus in ways that cannot be predicted from12 the individual receptor−ligand interactions alone. Here, we show13 that the intrinsic structural and energetic differences between the14 interactions of avian- or human-type receptors with influenza HA15 translate from individual site affinity and orientation through16 receptor length and density on the surface into virus avidity and17 specificity. We introduce a method to measure virus avidity using18 receptor density gradients. We found that influenza viruses attached stably to a surface at receptor densities that correspond to a19 minimum number of approximately 8 HA−glycan interactions, but more interactions were required if the receptors were short and20 human-type. Thus, the avidity and specificity of influenza viruses for a host cell depend not on the sialic acid linkage alone but on a21 combination of linkage and the length and density of receptors on the cell surface. Our findings suggest that threshold receptor22 densities play a key role in virus tropism, which is a predicting factor for both their virulence and zoonotic potential.