SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, XBB, emerged in late 2022, leading to descendant lineages with increased immune evasion and transmissibility.
• Understanding the structural basis of these adaptations is crucial for predicting viral evolution and developing countermeasures.

Purpose of the Study:

• To determine the cryoelectron microscopy (cryo-EM) structures of SARS-CoV-2 spike (S) ectodomains from key XBB lineage variants (XBB.1.5, XBB.1.16, EG.5, and EG.5.1).
• To elucidate the structural mechanisms underlying the enhanced immune evasion and transmissibility of these variants.

Main Methods:

• Cryoelectron microscopy (cryo-EM) was used to determine the structures of spike ectodomains from SARS-CoV-2 variants XBB.1.5, XBB.1.16, EG.5, and EG.5.1.
• Analysis focused on receptor-binding domain (RBD) conformations, interprotomer interactions, and the impact of specific mutations on S protein stability and presentation.

Main Results:

• Structures revealed reinforced closed states with receptor-inaccessible RBDs, mediated by interprotomer RBD interactions similar to BA.1 and BA.2.
• XBB.1.5 and XBB.1.16 demonstrated improved RBD stability, compensating for earlier Omicron mutations.
• The F456L substitution in EG.5 reduced RBD stability, while mutations in the S1 subunit influenced S2 subunit conformation and epitope presentation.

Conclusions:

• Continued evolution of the SARS-CoV-2 S protein involves simultaneous optimization of stability, receptor binding, and immune evasion.
• Relatively few residue substitutions can dramatically alter the S protein's conformational landscape, influencing viral properties.
• These findings provide insights into the structural adaptations driving the spread of recent SARS-CoV-2 variants.