How viruses switch between glycan and protein receptors and what it means for past and future pandemics

To enter a host cell a virus needs to bind a receptor on the cell surface. Typically, viruses use specialised glycoproteins to bind to either glycans or proteins as receptors. The specificity and affinity of a virus glycoprotein for cellular receptors is a key determinant for which hosts a virus can infect. Certain enveloped viruses of high pandemic potential, such as influenza A and coronaviruses, have an ability to change their receptor specificity from a glycan to a protein receptor, and in some instances, even bind both with one glycoprotein. These receptor transitions might have contributed to emergence of pandemic viruses, such as SARS-CoV-2, and may underlie future pandemics. Studying the structure and evolution of viral glycoproteins and their receptor complexes can help to understand the mechanisms viruses use to cross the human species barrier. I will build on my recent studies and pilot data on the structure and evolution of viral glycoproteins, and employ the glycoproteins of influenza viruses and coronaviruses which can bind to either or both receptor types to show: - how different receptor types are recognised structurally by very similar viral glycoproteins - how receptor type affects interaction avidity and mechanisms of viral fusion - how receptor transitions may arise during viral evolution and influence its direction This will be achieved by combining structural, biochemical, and biophysical approaches to reveal interactions between viral glycoproteins, influenza haemagglutinins and coronavirus spikes, with glycan and protein receptors. My studies will provide key new insights into the plasticity of viral glycoproteins and the evolutionary pathways associated with changes in receptor specificity, thus shedding light onto emergence of pandemic viruses such as SARS-CoV-2 and pandemic influenza A viruses. Importantly, this will also facilitate monitoring of emerging pathogens and increase our future pandemic preparedness.