The altered entry pathway and antigenic distance of the SARS-CoV-2 Omicron variant map to separate domains of spike protein
Thomas P Peacock, Jonathan C Brown, Jie Zhou, Nazia Thakur, Ksenia Sukhova, Joseph Newman, Ruthiran Kugathasan, Ada W C Yan, Wilhelm Furnon, Giuditta De Lorenzo, Vanessa M Cowton, Dorothee Reuss, Maya Moshe, Jessica L Quantrill, Olivia K Platt, Myrsini Kaforou, Arvind H Patel, Massimo Palmarini, Dalan Bailey, Wendy S Barclay
doi:10.1101/2021.12.31.474653
At the end of 2021 a new SARS-CoV-2 variant, Omicron, emerged and quickly spread across the world. It has been demonstrated that Omicron's high number of Spike mutations lead to partial immune evasion from even polyclonal antibody responses, allowing frequent re-infection and vaccine breakthroughs. However, it seems unlikely these antigenic differences alone explain its rapid growth; here we show Omicron replicates rapidly in human primary airway cultures, more so even than the previously dominant variant of concern, Delta. Omicron Spike continues to use human ACE2 as its primary receptor, to which it binds more strongly than other variants. Omicron Spike mediates enhanced entry into cells expressing several different animal ACE2s, including various domestic avian species, horseshoe bats and mice suggesting it has an increased propensity for reverse zoonosis and is more likely than previous variants to establish an animal reservoir of SARS-CoV-2. Unlike other SARS-CoV-2 variants, however, Omicron Spike has a diminished ability to induce syncytia formation. Furthermore, Omicron is capable of efficiently entering cells in a TMPRSS2-independent manner, via the endosomal route. We posit this enables Omicron to infect a greater number of cells in the respiratory epithelium, allowing it to be more infectious at lower exposure doses, and resulting in enhanced intrinsic transmissibility. .
Supplementary Figures Supplementary Figure S1
Supplementary Figure S2 -Different species ACE2 preference of different variants of concern. Receptor usage was screened using pseudoviruses expressing the indicated Spike proteins into 293Ts expressing the indicated ACE2 protein. Viral entry was measured by assaying luciferase activity (RLU) using the BrightGlo reagent (Promega).
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'abstract': '<jats:p>At the end of 2021 a new SARS-CoV-2 variant, Omicron, emerged and quickly spread '
'across the world. It has been demonstrated that Omicrons high number of Spike mutations lead '
'to partial immune evasion from even polyclonal antibody responses, allowing frequent '
're-infection and vaccine breakthroughs. However, it seems unlikely these antigenic '
'differences alone explain its rapid growth; here we show Omicron replicates rapidly in human '
'primary airway cultures, more so even than the previously dominant variant of concern, Delta. '
'Omicron Spike continues to use human ACE2 as its primary receptor, to which it binds more '
'strongly than other variants. Omicron Spike mediates enhanced entry into cells expressing '
'several different animal ACE2s, including various domestic avian species, horseshoe bats and '
'mice suggesting it has an increased propensity for reverse zoonosis and is more likely than '
'previous variants to establish an animal reservoir of SARS-CoV-2. Unlike other SARS-CoV-2 '
'variants, however, Omicron Spike has a diminished ability to induce syncytia formation. '
'Furthermore, Omicron is capable of efficiently entering cells in a TMPRSS2-independent '
'manner, via the endosomal route. We posit this enables Omicron to infect a greater number of '
'cells in the respiratory epithelium, allowing it to be more infectious at lower exposure '
'doses, and resulting in enhanced intrinsic transmissibility.</jats:p>',
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