Glycan- and protein-based receptor usage of endemic human coronaviruses – host-specific adaptations and implications for embecoviral cross-species transmission

• Applicant: Dr. Robert Creutznacher
• Subject Area: Virology ; Structural Biology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 494746248

Four coronaviruses of zoonotic origin have successfully established themselves as endemic human pathogens. Two of these endemic coronaviruses, grouped together in the subgenus Embecovirus, have independently developed a strategy for invasion of the host’s airway epithelium that is unique among human coronaviruses: attachment to sialic acid-bearing cell surface glycans via their spike proteins. Apparently, their zoonotic spillover was accompanied by substantial changes in glycan binding affinity as an adaptive adjustment to a different carbohydrate composition within the novel host. Given the abundance of closely related embecoviruses in domestic animals, this highly successful evolutionary trait for coronavirus cross-species transmission deserves closer scrutiny. Sequence analysis of contemporary embecovirus spike proteins hints at further adaptive changes during their subsequent evolutionary trajectory but almost nothing is known about the specific glycan binding properties of circulating embecovirus field strains. I propose to study the principles of cell surface interactions of clinically relevant strains of the embecovirus OC43 by a combination of structural, biophysical and functional methods. In particular, I am aiming to obtain a structural model of the glycan-bound state of a contemporary OC43 spike protein using cryo-electron microscopy. I will characterize the preference of these viruses for specific carbohydrates and compare these findings with those of its zoonotic ancestor. Additionally, compelling evidence suggests the existence of a so-far unknown secondary, protein-based embecovirus receptor. I will attempt to identify this receptor and shine light on its role in the complex mode of embecoviral cell attachment. Taken together, this project will further our understanding of how coronavirus-glycan interactions have been exploited during adaptation to human hosts and elucidate the essential binding properties required for zoonotic spillover of embecoviruses.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Host: Professor Dr. Raoul J. de Groot