Statistical Binding Matching between Influenza A Virus and Dynamic Glycan Clusters Determines Its Adhesion onto Lipid Membranes

The resistance of drugs to the new influenza A virus (IAV) strains and the limited efficiency of vaccines to prevent seasonal flu epidemics underscore the urgency in finding novel strategies to block IAV infection, which is required to gain insights into the mechanism of the initial step of IAV adhesion. While it is well established that IAVs bind to respiratory tract cells by recognizing sialylated glycans on host cell membranes through a multivalency effect, how IAVs dynamically respond to multiple glycan receptors via distinct valencies has not been fully understood, limiting the discovery of novel anti-flu strategies. Using single-particle tracking to record the 2D mobilities and surface residence times of highly pathogenic H5N1 avian IAVs adhered to fluidic membranes containing alpha 2-3 sialylated GM3 glycolipids, we quantified the univalent and multivalent IAV adhesion channels, which provide insights into the mechanism of IAV binding; IAV can guide the clustering of dynamic glycolipids to statistically match the multivalent binding affinities for IAV adhesion. This mechanism can be inhibited by disrupting the dynamic glycan clustering on membranes of varying fluidities, like the gel phase membrane. This work facilitates a deeper fundamental understanding of IAV infection as well as the development of novel anti-flu strategies.