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
- Copenhagen University Hospital, Denmark
- Novo Nordisk A/S, Denmark
- Aarhus University, Denmark
- Aarhus University Hospital, Denmark
Abstract
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 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 eight-fold affinity increase towards human ACE-2. In accordance with this, transgenic hACE-2 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. We have no restrictions with regards to data availability.
Article and author information
Author details
Mikkel-Ole Skjoedt
Funding
Carlsbergfondet (CF20-0045)
- Rafael Bayarri-Olmos
- Anne Rosbjerg
- Peter Garred
- Mikkel-Ole Skjoedt
Novo Nordisk Fonden (NFF205A0063505)
- Rafael Bayarri-Olmos
- Anne Rosbjerg
- Peter Garred
- Mikkel-Ole Skjoedt
Novo Nordisk Fonden (NNF20OC0063436)
- Rafael Bayarri-Olmos
- Anne Rosbjerg
- Peter Garred
- Mikkel-Ole Skjoedt
Novo Nordisk Fonden (NNF20SA0064201)
- Rafael Bayarri-Olmos
- Anne Rosbjerg
- Peter Garred
- Mikkel-Ole Skjoedt
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The Danish Animal Experiments Inspectorate has approved the experimental animal procedures and were carried out in accordance with the Danish Animal Welfare Act for the Care and Use of Animals for Scientific Purposes. (License ID 2019-15-0201-00090 and 2020-15-0201-00726). All procedures followed the recommendations of the Animal Facilities at the Universities of Copenhagen and Aarhus.
Human subjects: The collection and use of blood samples have been approved by the Regional Ethical Committee of the Capital Region of Denmark (H-20028627) and (H-20079890). The human studies were conducted in agreement with the Helsinki declaration. We have received informed consent to do the examinations included in this study including to publish data.
Copyright
© 2021, Bayarri-Olmos et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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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 10:e70002.
https://doi.org/10.7554/eLife.70002
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During parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.
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