Journal
CELL RESEARCH
Volume 32, Issue 7, Pages 609-620Publisher
SPRINGERNATURE
DOI: 10.1038/s41422-022-00672-4
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Funding
- Ministry of Science and Technology (China) [2018YFA0507002]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Shanghai Municipal Science and Technology Major Project
- CAS Strategic Priority Research Program [XDB37030103]
- National Natural Science Foundation of China [32130022, 32171189, 81902085]
- Youth Innovation Promotion Association of CAS [2021278]
- National Science Fund for Excellent Young Scholars [82122067]
- Key tasks of the Lingang Laboratory [LG202103-03-05, LG202101-01-03]
- China Postdoctoral Science Foundation [2021M703342]
- Shanghai Post-doctoral Excellence Program [2021429]
- High-level Innovative Research Institute from Department of Science and Technology of Guangdong Province [2021B0909050003]
- Sanofi Scholarship Program
- High-level new R&D institute from Department of Science and Technology of Guangdong Province [2019B090904008]
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The Omicron BA.2 variant is a highly infectious strain that shows increased binding potency to human ACE2 compared to other strains. The therapeutic antibody, JMB2002, inhibits both Omicron BA.1 and BA.2 effectively. The interaction between the BA.1 and BA.2 spike trimers and mouse ACE2 provides insights into their high affinity. The results suggest a possible evolutionary pathway for the Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle.
The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to efficiently inhibit Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle, which could have important implications in establishing an effective strategy for combating SARS-CoV-2 viral infections.
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