Influenza A virus receptor engagement

a complex dance with multiple partners

Influenza A viruses are perhaps the best-known viruses that use glycans to initiate infection. Glycan specificities of different influenza viruses dictate infectivity and host range. To be prepared for drifting human viruses and potential zoonotic infections, a deep understanding of glycan binding properties is vital. As virus-glycan interactionstake place on a complex cell membrane, where multiple virus protein-cell receptor interaction pairs form and break in a dynamic manner, our current analyses of glycan binding properties fail. The overall binding avidity and selectivity are governed not only by the individual affinities between virus proteins and glycans but are the result of the multivalent complex and all molecular and structural aspects that contribute to its formation. This hierarchical molecular picture is currently still sketchy. Many details are lacking, for example, how the orientational difference in binding between a 2,3 vs 2,6-glycan in the HA binding pocket is translated into multiple HA-glycan pairs at the interface, when viewing the linkers, attachments and densities that are involved in both binding partners. This project aims to elucidate these structural elements that contribute to the binding interface by designing, synthesizing and testing various HA constructs and glycan-modified cell surface mimics, measure their interactions, and model their overall binding behaviour using multivalency and super-selectivity theory. We will do this for HA proteins of different virus strains to be able to correlate the multivalent binding behaviour to biological aspects such as selectivity and mutational responses to immunity and drugs. The approaches presented here are unique as they bring together state-ofthe-art molecular biology and surface chemistry. Thus, we will answer long standing biological questions in the field of how IAV interacts with cell surface glycans, giving templates for the design of novel receptor binding techniques and antivirals to block these.

Contact 
María Ríos Carrasco