Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

McCallum, Matthew; Czudnochowski, Nadine; Rosen, Laura E.; Zepeda, Samantha K; Bowen, John E.; Walls, Alexandra C.; Hauser, Kevin; Joshi, Anshu; Stewart, Cameron; Dillen, Josh R; Chen, Alex; Croll, Tristan I.; Nix, Jay C.; Virgin, Herbert W.; Corti, Davide; Snell, Gyorgy; Veesler, David

doi:10.1126/science.abn8652

Cited by 483 publications

(524 citation statements)

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“…To explore the cause of epistasis between Q498R and N501Y (Fig. 3A), we examined structures of Wuhan-Hu-1 and Omicron RBDs bound to ACE2 ( 12 , 23 ) complemented by molecular dynamics simulation (Fig. 4C,D and Fig.…”

Section: Main Textmentioning

confidence: 99%

Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution

Starr

Greaney

Hannon

et al. 2022

Preprint

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SARS-CoV-2 has evolved variants with substitutions in the spike receptor-binding domain (RBD) that impact its affinity for ACE2 receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites--a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single amino-acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently N501Y, cause epistatic shifts in the effects of mutations at other sites, thereby shaping subsequent evolutionary change. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.

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Section: Main Textmentioning

confidence: 99%

Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution

Starr

Greaney

Hannon

et al. 2022

Preprint

Self Cite

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“…However, the extent that this decreased severity can be attributed to viral factors, as opposed to immunization status, for example, remains to be determined. Nonetheless, the organoid models were predictive of immune evasion by Omicron [52], the structural basis of which has recently been attributed to specific mutations in the S protein [235].…”

Section: Clinical Isolates and Viral Stocksmentioning

confidence: 99%

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which was classified as a pandemic in March 2020. As of 22 January 2022, globally more than 347 million cases of COVID-19 have been diagnosed, with 5.6 million deaths, making it the deadliest pandemic since the influenza pandemic in 1918. The clinical presentation of COVID-19-related illness spans from asymptomatic to mild respiratory symptoms akin to influenza infection to acute symptoms, including pneumonia necessitating hospitalisation and admission to intensive care units. COVID-19 starts in the upper respiratory tract and lungs but in severe cases can also involve the heart, blood vessels, brain, liver, kidneys and intestine. The increasing global health and economic burden of COVID-19 necessitates an urgent and global response. Understanding the functional characteristics and cellular tropism of SARS-CoV-2, and the pathogenesis that leads to multi-organ failure and death, has prompted an unprecedented adoption of organoid models. Successful drug discovery and vaccine development rely on pre-clinical models that faithfully recapitulate the viral life cycle and the host cell response to infection. Human stem cell-derived organoids fulfill these criteria. Here we highlight the role of organoids in the study of SARS-CoV-2 infection and modelling of COVID-19 pathogenesis.

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“…The Omicron variant harbors a remarkable 59–amino acid substitution throughout its genome relative to the ancestral Wuhan-hu-1 SARS-CoV-2 virus, where almost 37 of these nonsynonymous mutations are located within the spike protein, the target of neutralizing antibodies against SARS-CoV-2 [ 10 ]. Overall, emerging data have suggested that the omicron variant presents increased transmissibility and ability to dodge immunity whether from vaccination or previous infection as well decreased pathogenicity [ 11 , 12 ]. In the meantime, the Omicron sub-lineage BA.2 has already been identified with an even faster growth rate.…”

Section: Introductionmentioning

confidence: 99%