Structural evolution of SARS-CoV-2 omicron in human receptor recognition.

Area of Science:

• Virology
• Structural Biology
• Evolutionary Biology

Background:

• The ongoing evolution of SARS-CoV-2 omicron subvariants presents challenges to pandemic control.
• Understanding the molecular mechanisms driving omicron's adaptation is critical for predicting future viral trajectories.

Purpose of the Study:

• To elucidate the structural adaptations of SARS-CoV-2 omicron subvariants' receptor-binding domains (RBDs).
• To investigate the roles of non-human animals and immune evasion in omicron's evolutionary history.

Main Methods:

• Determined crystal structures of RBDs from omicron subvariants (XBB.1, XBB.1.5, XBB.1.9.1) complexed with human ACE2.
• Analyzed structural changes in RBD residues and their adaptation to human and mouse ACE2.

Main Results:

• Specific RBD residues (e.g., 493, 496) showed shifts in human ACE2 adaptation, correlating with mouse ACE2 adaptation in early omicron, suggesting a role for non-human animals.
• Residue 486 adaptation varied, with later changes potentially linked to immune evasion, indicating distinct evolutionary pressures at different stages.

Conclusions:

• Non-human animal hosts may have facilitated the evolution of early omicron subvariants.
• Immune evasion appears to be a significant driver for the evolution of later omicron subvariants.
• Combined pressures from non-human animals and immune evasion shaped the evolutionary trajectory of SARS-CoV-2 omicron.