The impact of S2 mutations on Omicron SARS-CoV-2 cell surface expression and fusogenicity.

Autor:	Escalera A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Laporte M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Turner S; Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK., Karakus U; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Gonzalez-Reiche AS; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., van de Guchte A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Farrugia K; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Khalil Z; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., van Bakel H; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Smith D; Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK., García-Sastre A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Aydillo T; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	Emerging microbes & infections [Emerg Microbes Infect] 2024 Dec; Vol. 13 (1), pp. 2297553. Date of Electronic Publication: 2024 Feb 13.
DOI:	10.1080/22221751.2023.2297553
Abstrakt:	SARS-CoV-2 Omicron subvariants are still emerging and spreading worldwide. These variants contain a high number of polymorphisms in the spike (S) glycoprotein that could potentially impact their pathogenicity and transmission. We have previously shown that the S:655Y and P681H mutations enhance S protein cleavage and syncytia formation. Interestingly, these polymorphisms are present in Omicron S protein. Here, we characterized the cleavage efficiency and fusogenicity of the S protein of different Omicron sublineages. Our results showed that Omicron BA.1 subvariant is efficiently cleaved but it is poorly fusogenic compared to previous SARS-CoV-2 strains. To understand the basis of this phenotype, we generated chimeric S protein using combinations of the S1 and S2 domains from WA1, Delta and Omicron BA.1 variants. We found that the S2 domain of Omicron BA.1 hindered efficient cell-cell fusion. Interestingly, this domain only contains six unique polymorphisms never detected before in ancestral SARS-CoV-2 variants. WA1 614G S proteins containing the six individuals S2 Omicron mutations were assessed for their fusogenicity and S surface expression after transfection in cells. Results showed that the S:N856K and N969K substitutions decreased syncytia formation and impacted S protein cell surface levels. However, we observed that "first-generation" Omicron sublineages that emerged subsequently, had convergently evolved to an enhanced fusogenic activity and S expression on the surface of infected cells while "second-generation" Omicron variants have highly diverged and showed lineage-specific fusogenic properties. Importantly, our findings could have potential implications in the improvement and redesign of COVID-19 vaccines.
Databáze:	MEDLINE
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