Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins

Abstract

The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies reveal that the BA.2 spike trimer have 11-fold and 2-fold higher potency to human ACE2 than the spike trimer from the wildtype and Omicron BA.1 strains. The structure of the BA.2 spike timer reveals that all three receptor-binding domains (RBD) in the spike trimer are in open conformation, ready for high affinity binding to human ACE2, providing the basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to have efficient inhibition of 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 the mouse ACE2 with high potency. In contrast, the wildtype 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 from human-cat-mouse-human circle, which could have important implications in establishing an effective strategy in combating viral infection.

Characterization of entry pathways, species-specific ACE2 residues determining entry, and antibody neutralization evasion of Omicron BA.1, BA.1.1, BA.2, and BA.3 variants

“…Our data further show that Omicron lineage spike proteins more efficiently use ACE2 receptors from diverse animal species for entry. Our findings showing Omicron lineage spikes’ usage of mouse ACE2 for entry extend previous reports showing enhanced binding of BA.1 and BA.2 RBD to mouse ACE2 3,57 . Similar (K417N, N501Y, Q493H/R) 33,50,58 or closely related (Q498H) 50,59 mouse-adapted substitutions previously found in experimentally infected mice are observed in Omicron RBM that may contribute to binding to mouse ACE2.…”

“…Substitutions proximal to the furin cleavage site (H655Y, N679K and P681H), as well as substitutions in the S2 subunit, may contribute to less efficient TMPRSS2 cleavage of Omicron spike 36 . Finally, higher affinities of BA.1 (6-fold) and BA.2 (11-fold) RBD for ACE2 coupled with transitions into the so called two- or three-RBD-up conformations may also contribute to the efficient use of ACE2 48,57 . In the present study, we report higher but similar sensitivities for BA.1, BA.2, and BA.1.1 to inhibition by the soluble ACE2 monomer (3-fold vs D614G) while BA.3 and D614G are comparably less sensitive.…”

Characterization of Entry Pathways, Species-Specific Angiotensin-Converting Enzyme 2 Residues Determining Entry, and Antibody Neutralization Evasion of Omicron BA.1, BA.1.1, BA.2, and BA.3 Variants

“…Our data further show that all four Omicron lineage spike proteins more efficiently use ACE2 receptors from diverse animal species for entry. Our findings showing Omicron lineage spikes’ use of mouse ACE2 for entry extend previous reports showing enhanced binding of BA.1 and BA.2 RBD to mouse ACE2 ( 3 , 58 ). Similar (K417N, N501Y, Q493H/R) ( 33 , 50 , 60 ) or closely related (Q498H) ( 50 , 61 ) mouse-adapted substitutions previously found in experimentally infected mice are observed in Omicron RBM that may contribute to binding to mouse ACE2.…”

“…Substitutions proximal to the furin cleavage site (H655Y, N679K, and P681H), as well as substitutions in the S2 subunit, may reduce efficiency of TMPRSS2 cleavage of the Omicron spikes ( 36 ). Finally, higher affinities of BA.1 (6-fold) and BA.2 (11-fold) RBD for ACE2 coupled with transitions into the so called two- or three-RBD-up conformations may also contribute to the efficient use of ACE2 ( 48 , 58 , 59 ). In the present study, we report that BA.1, BA.2, and BA.1.1 were similarly inhibited by the soluble ACE2 monomer (3-fold versus D614G), while BA.3 and D614G were comparably less sensitive.…”