How using glycans vs. proteins as receptors affects the mechanism of viral entry (360G-Wellcome-303026_Z_23_Z)

Viruses typically employ either glycans or proteins as receptors. However, certain viruses, such as influenza A and coronaviruses, have the ability to alter their receptor specificity—from a glycan to a protein receptor, and in some instances, even bind both. These receptor transitions can correlate with changes in viral tropism, influencing disease severity and facilitating host jumps. Yet, little is known about the effects the receptor type have on the mechanism of viral entry. I will use my background in studying the structure and evolution of viral glycoproteins to compare at the molecular level how different receptor types are recognised structurally, how they dictate interaction avidity, and affect the mechanisms of viral fusion. We will build on my pilot data on interactions between haemagglutinins of bat-like influenza viruses and their non-canonical protein receptors MHC-IIs, and new structural insights into coronavirus spikes, to investigate and compare mechanisms of binding between influenza haemagglutinins and coronavirus spikes with glycan and protein receptors. This will bring new insights into the mechanisms of viral entry and reveal possible evolutionary pathways associated with changes in receptor tropism, enabling informed monitoring of emerging viruses and contributing to pandemic prevention.