Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness.

Area of Science:

• Virology
• Molecular Biology
• Evolutionary Biology

Background:

• Sarbecoviruses exhibit diverse receptor binding motif (RBM) structures.
• Understanding ACE2 adaptiveness across species is crucial for assessing spillover risks.

Purpose of the Study:

• To analyze the impact of RBM insertions/deletions (indels) on sarbecovirus ACE2 usage.
• To investigate the relationship between RBM indel types and ACE2 tropism in various mammalian species.

Main Methods:

• Analysis of 268 sarbecovirus RBM sequences categorized into four indel types.
• Examination of Spike glycoprotein-mediated ACE2 utilization by 20 representative sarbecoviruses and derivatives.
• Assessment of ACE2 usage across bat and other mammalian species.

Main Results:

• Sarbecoviruses with long RBMs (type-I) demonstrate broad ACE2 tropism.
• Viruses with single RBM deletions (type-II and type-III) exhibit narrower ACE2 tropism.
• Sarbecoviruses with double RBM deletions (type-IV) lose ACE2 usage, influenced by clade-specific residues.

Conclusions:

• RBM indel types significantly dictate sarbecovirus ACE2 adaptiveness and host tropism.
• Loop lengths, disulfide bonds, and residue determinants critically shape multi-species ACE2 utilization.
• Insights into RBM evolution and ACE2 binding mechanisms inform potential spillover risk assessments.