Hierarchical Multivalent Effects Control Influenza Host Specificity

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.