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The impact of S2 mutations on Omicron SARS-CoV-2 cell surface expression and fusogenicity.
Escalera, Alba; Laporte, Manon; Turner, Sam; Karakus, Umut; Gonzalez-Reiche, Ana S; van de Guchte, Adriana; Farrugia, Keith; Khalil, Zain; van Bakel, Harm; Smith, Derek; García-Sastre, Adolfo; Aydillo, Teresa.
Affiliation
  • Escalera A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Laporte M; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Turner S; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Karakus U; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Gonzalez-Reiche AS; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • van de Guchte A; Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
  • Farrugia K; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Khalil Z; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • van Bakel H; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Smith D; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • García-Sastre A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Aydillo T; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Emerg Microbes Infect ; 13(1): 2297553, 2024 Dec.
Article in En | MEDLINE | ID: mdl-38112266
ABSTRACT
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 S655Y 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. WA1614G 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 SN856K 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: COVID-19 Vaccines / COVID-19 Limits: Humans Language: En Journal: Emerg Microbes Infect Year: 2024 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: COVID-19 Vaccines / COVID-19 Limits: Humans Language: En Journal: Emerg Microbes Infect Year: 2024 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos