The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice
The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the recep...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/70002 |
| _version_ | 1811236011450040320 |
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| author | Rafael Bayarri-Olmos Laust Bruun Johnsen Manja Idorn Line S Reinert Anne Rosbjerg Søren Vang Cecilie Bo Hansen Charlotte Helgstrand Jais Rose Bjelke Theresa Bak-Thomsen Søren R Paludan Peter Garred Mikkel-Ole Skjoedt |
| author_facet | Rafael Bayarri-Olmos Laust Bruun Johnsen Manja Idorn Line S Reinert Anne Rosbjerg Søren Vang Cecilie Bo Hansen Charlotte Helgstrand Jais Rose Bjelke Theresa Bak-Thomsen Søren R Paludan Peter Garred Mikkel-Ole Skjoedt |
| author_sort | Rafael Bayarri-Olmos |
| collection | DOAJ |
| description | The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant. |
| first_indexed | 2024-04-12T12:02:07Z |
| format | Article |
| id | doaj.art-0dacfd22c5c844a6adf835fea181b896 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:02:07Z |
| publishDate | 2021-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0dacfd22c5c844a6adf835fea181b8962022-12-22T03:33:49ZengeLife Sciences Publications LtdeLife2050-084X2021-11-011010.7554/eLife.70002The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 miceRafael Bayarri-Olmos0Laust Bruun Johnsen1Manja Idorn2Line S Reinert3Anne Rosbjerg4Søren Vang5Cecilie Bo Hansen6Charlotte Helgstrand7Jais Rose Bjelke8Theresa Bak-Thomsen9Søren R Paludan10Peter Garred11https://orcid.org/0000-0002-2876-8586Mikkel-Ole Skjoedt12https://orcid.org/0000-0003-1306-6482Recombinant Protein and Antibody Laboratory, Copenhagen University Hospital, Copenhagen, Denmark; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, DenmarkNovo Nordisk A/S, Måløv, DenmarkDepartment of Biomedicine, Aarhus University, Århus, DenmarkDepartment of Biomedicine, Aarhus University, Århus, DenmarkRecombinant Protein and Antibody Laboratory, Copenhagen University Hospital, Copenhagen, Denmark; Institute of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkDepartment of Molecular Medicine, Aarhus University Hospital, Aarhus, DenmarkLaboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, DenmarkNovo Nordisk A/S, Måløv, DenmarkNovo Nordisk A/S, Måløv, DenmarkNovo Nordisk A/S, Måløv, DenmarkDepartment of Biomedicine, Aarhus University, Århus, DenmarkLaboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, DenmarkLaboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; Institute of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkThe alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.https://elifesciences.org/articles/70002immunologyepidemiologySARS-CoV-2mouse modelhuman |
| spellingShingle | Rafael Bayarri-Olmos Laust Bruun Johnsen Manja Idorn Line S Reinert Anne Rosbjerg Søren Vang Cecilie Bo Hansen Charlotte Helgstrand Jais Rose Bjelke Theresa Bak-Thomsen Søren R Paludan Peter Garred Mikkel-Ole Skjoedt The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice eLife immunology epidemiology SARS-CoV-2 mouse model human |
| title | The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice |
| title_full | The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice |
| title_fullStr | The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice |
| title_full_unstemmed | The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice |
| title_short | The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice |
| title_sort | alpha b 1 1 7 sars cov 2 variant exhibits significantly higher affinity for ace 2 and requires lower inoculation doses to cause disease in k18 hace2 mice |
| topic | immunology epidemiology SARS-CoV-2 mouse model human |
| url | https://elifesciences.org/articles/70002 |
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