Hierarchical Multivalent Effects Control Influenza Host Specificity

Abstract

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.

A Dynamic, Supramolecular View on the Multivalent Interaction between Influenza Virus and Host Cell

“…a) IAV binds to glycoproteins and glycolipids on a host cell membrane through its surface glycoproteins HA and NA. The image is not to scale; the virus is 100-150 nm, [7] HA and NA are ≈14 and ≈16 nm long, [7] the lipid membrane is ≈5 nm thick, [12] glycans are 2-20 nm, [10,13] mucins and cilia ( Figure 10) are omitted. b) HA forms reversible interactions with sialoglycan receptors, whereas NA can bind the same receptors and cleave the sialic acid.…”

“…[22][23][24] The receptor density is directly related to the multivalent binding affinity. [13] The highest selectivity is achieved with a high number of interactions that are individually weak, with binding energies on the order of the thermal energy k B T. [25] Additionally, even higher selectivities can be achieved when there are polymers on the particle or surface that give steric repulsion. [26,27] We have developed a theoretical binding model based on the statistical thermodynamics of multivalent adsorption of IAV to a surface with short glycans.…”

“…A BLI machine can process 96-or 384-well Reproduced with permission. [13] Copyright 2020, American Chemical Society.…”

“…[45,66] The density of receptors can be controlled by varying the loading time or concentration, or by diluting the receptors with a dummy receptor. [13,45,66] The resulting binding profiles as a function of relative sugar loading are used as a relative measure of virus avidity. When a virus is titrated to determine K D , values can differ by two orders of magnitude, depending on the relative sugar loading.…”

“…The virus binding profile shows Equation 2 fitted (yellow S-curve) over a density map of data points (N ≈ 400 000 from three pairs of micrographs). Reproduced with permission under CC-BY-NC-ND 4.0 [13]. Copyright 2020, American Chemical Society.…”