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

• Final Report Year: 2024

Final Report Abstract

This project focused on two human coronaviruses, OC43 and HKU1, which use modified sialic acids as entry receptors. These viruses, although causing mild diseases, share a common dependence on such sialoglycans for infection, making them a model for studying cross-species transmission of glycan-dependent viruses and long-term adaptation to the human host. We revealed that HKU1 uses a dual-receptor strategy: The virus first binds to sialoglycans, which then triggers a conformational change in its spike (S) protein, exposing a binding site for a secondary protein receptor. This sequential, dual-receptor mechanism has not been observed in any coronavirus before and priming of entry may also offer a means of immune escape. HKU1 shows a strong preference for α2,8-linked sialoglycans, which we identified as part of specific gangliosides in human nasal epithelial cells. This selective binding is a determinant of viral tropism and essential for the virus’s attachment and entry into host cells. Over time, OC43 has adapted to the human respiratory tract by progressively losing affinity for sialoglycans. This adaptation mirrors the loss of the hemagglutinin-esterase (HE) lectin domain, highlighting the co-evolution of coronaviral proteins to balance attachment and motility. Understanding how coronaviruses like OC43 and HKU1 adapt to human hosts and utilize specific receptors for infection is crucial to build up pandemic preparedness and can inform the design of novel vaccines and antiviral drugs.

Publications

• Sialoglycan binding triggers spike opening in a human coronavirus. Nature, 624(7990), 201-206.
  Pronker, Matti F.; Creutznacher, Robert; Drulyte, Ieva; Hulswit, Ruben J. G.; Li, Zeshi; van Kuppeveld, Frank J. M.; Snijder, Joost; Lang, Yifei; Bosch, Berend-Jan; Boons, Geert-Jan; Frank, Martin; de Groot, Raoul J. & Hurdiss, Daniel L.