Design of customized coronavirus receptors

Area of Science:

• Virology
• Molecular Biology
• Infectious Diseases

Background:

• Characterizing coronaviruses is challenging due to diverse receptors and a lack of infection models for those with unknown receptors.
• Existing models are insufficient for studying many coronaviruses, hindering research into their biology and pathogenesis.

Purpose of the Study:

• To engineer functional customized viral receptors (CVRs) that mimic native receptors.
• To establish native receptor-independent infection models for a broad range of coronaviruses.
• To facilitate the study of coronaviruses with unknown or uncharacterized receptors.

Main Methods:

• Designed modular artificial receptor scaffolds with specific virus-binding domains.
• Identified key factors for CVRs to mimic native receptor functions, including spike proteolytic cleavage and membrane fusion.
• Generated CVR-expressing cells for 12 representative coronaviruses and tested their infectivity and propagation.

Main Results:

• Demonstrated that CVRs can functionally mimic native receptors, supporting pseudovirus entry and propagation for various coronaviruses.
• Showcased a pan-sarbecovirus CVR that supports the propagation of pseudotyped and authentic sarbecoviruses.
• Successfully rescued and propagated HKU5 coronavirus using a specific CVR, and isolated a bat-derived HKU5 strain.

Conclusions:

• The customized viral receptor (CVR) strategy provides a versatile tool for creating infection models for coronaviruses lacking known receptors.
• This approach overcomes limitations in studying viruses with unknown cellular targets, advancing coronavirus research.
• Enables the investigation of diverse coronaviruses, including those previously difficult to culture or study.