Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins

Abstract

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.

Immune Escape Associated with RBD Omicron Mutations and SARS-CoV-2 Evolution Dynamics

“…Alternatively, it was shown that the Wuhan strain binds with a good specificity to cat ACE2, but not to mouse ACE2. Considering the fact that the Omicron strain efficiently binds both the murine and the human ACE2-receptors, the possible evolution pathway could be the following: human–cat–mouse–human [ 21 ]. Thus, an inter-species evolutionary trajectory for the Omicron outbreak is possible [ 20 , 21 ].…”

“…Considering the fact that the Omicron strain efficiently binds both the murine and the human ACE2-receptors, the possible evolution pathway could be the following: human–cat–mouse–human [ 21 ]. Thus, an inter-species evolutionary trajectory for the Omicron outbreak is possible [ 20 , 21 ]. In addition, immunocompromised HIV-infected patients could be favorable hosts for SARS-CoV-2 evolution [ 22 , 23 ].…”

Omicron BA.2 Lineage, the “Stealth” Variant: Is It Truly a Silent Epidemic? A Literature Review

“…It is known that the Omicron variant has a higher affinity for the ACE2 receptor and, consequentially, the potential for increased transmission [2]. The hACE2 receptor bound to the Omicron BA.2 spike trimer with a dissociation constant approximately 11-fold higher than that for the WT spike trimer and nearly 2-fold higher than that for the BA.1 spike trimer [29]. Among the Omicron sub-lineages, BA.2 and BA.3 have higher transmission potentials compared to BA.1: BA.2 has a docking energy of −974, which is higher than that of BA1.1 (−946.8) and BA.1 (−943.4) but lower than that of BA.3 (−999.3) [12].…”

Vitamin C is an efficient natural product for prevention of SARS-CoV-2 infection by targeting ACE2 in both cell and in vivo mouse models

“…Particularly, ACE2 has a 10-20-fold higher affinity to the Spike protein of SARS-CoV-2 than to that of SARS-CoV (Wrapp et al, 2020), which could suggest the severity of SARS-CoV-2-induced coronavirus disease 2019 (COVID-19). In addition, the recently prevalent SARS-CoV-2 mutant Omicron has produced much stronger infectivity, because the Spike trimer of Omicron (BA.2) exhibits 11-fold higher potency in binding to human ACE2 than that of the wild-type (WT) SARS-CoV-2 (Xu et al, 2022). Thus, ACE2 is the key target to control the infection of SARS-CoV-2 and even its current and future mutants.…”