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A novel isoform of ACE2 is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

View ORCID ProfileCornelia Blume, View ORCID ProfileClaire L Jackson, Cosma Mirella Spalluto, View ORCID ProfileJelmer Legebeke, View ORCID ProfileLiliya Nazlamova, View ORCID ProfileFranco Conforti, View ORCID ProfileJeanne-Marie Perotin-Collard, View ORCID ProfileMartin Frank, View ORCID ProfileMax Crispin, Janice Coles, James Thompson, Robert A Ridley, Lareb S N Dean, View ORCID ProfileMatthew Loxham, View ORCID ProfileAdnan Azim, Kamran Tariq, David Johnston, View ORCID ProfilePaul J Skipp, View ORCID ProfileRatko Djukanovic, View ORCID ProfileDiana Baralle, Chris McCormick, View ORCID ProfileDonna E Davies, View ORCID ProfileJane S Lucas, View ORCID ProfileGabrielle Wheway, View ORCID ProfileVito Mennella
doi: https://doi.org/10.1101/2020.07.31.230870
Cornelia Blume
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Claire L Jackson
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
3Institute for Life Sciences, University of Southampton, Southampton, UK
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Cosma Mirella Spalluto
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
4Wessex Investigational Sciences Hub, Faculty of Medicine, University of Southampton Faculty of Medicine, Southampton, UK
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Jelmer Legebeke
5School of Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
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Liliya Nazlamova
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
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Franco Conforti
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Jeanne-Marie Perotin-Collard
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
6Service de Pneumologie, INSERM U1250, Hôpital Universitaire, Reims, France
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Martin Frank
7Biognos AB, Generatorsgatan 1, Box 8963, 40274 Göteborg, Sweden
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Max Crispin
3Institute for Life Sciences, University of Southampton, Southampton, UK
8School of Biological Sciences, University of Southampton Faculty of Environmental and Life Sciences Southampton, UK
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Janice Coles
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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James Thompson
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Robert A Ridley
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Lareb S N Dean
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Matthew Loxham
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Adnan Azim
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Kamran Tariq
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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David Johnston
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
9Biomedical Imaging Unit, Faculty of Medicine, University of Southampton, Southampton, UK
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Paul J Skipp
3Institute for Life Sciences, University of Southampton, Southampton, UK
8School of Biological Sciences, University of Southampton Faculty of Environmental and Life Sciences Southampton, UK
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Ratko Djukanovic
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Diana Baralle
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
5School of Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
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Chris McCormick
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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Donna E Davies
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
3Institute for Life Sciences, University of Southampton, Southampton, UK
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  • For correspondence: d.e.davies@soton.ac.uk jlucas1@soton.ac.uk g.wheway@soton.ac.uk v.mennella@soton.ac.uk
Jane S Lucas
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
3Institute for Life Sciences, University of Southampton, Southampton, UK
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  • For correspondence: d.e.davies@soton.ac.uk jlucas1@soton.ac.uk g.wheway@soton.ac.uk v.mennella@soton.ac.uk
Gabrielle Wheway
3Institute for Life Sciences, University of Southampton, Southampton, UK
5School of Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
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  • For correspondence: d.e.davies@soton.ac.uk jlucas1@soton.ac.uk g.wheway@soton.ac.uk v.mennella@soton.ac.uk
Vito Mennella
1School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
2Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
3Institute for Life Sciences, University of Southampton, Southampton, UK
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  • For correspondence: d.e.davies@soton.ac.uk jlucas1@soton.ac.uk g.wheway@soton.ac.uk v.mennella@soton.ac.uk
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Abstract

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in the airways for SARS-CoV-2. ACE2 binding to SARS-CoV-2 protein Spike triggers viral fusion with the cell membrane, resulting in viral RNA genome delivery into the host. Despite ACE2’s critical role in SARS-CoV-2 infection, an understanding of ACE2 expression, including in response to viral infection, remains unclear.

Until now ACE2 was thought to encode five transcripts and one 805 amino acid protein. Here we identify a novel short isoform of ACE2. Short ACE2 is expressed in the airway epithelium, the main site of SARS-CoV-2 infection; it is substantially upregulated in response to interferon stimulation and RV infection, but not in response to SARS-CoV-2 infection, and it shows differential regulation in asthma patients. This short isoform lacks SARS-CoV-2 spike glycoprotein high-affinity binding sites and altogether, our data are consistent with a model where short ACE2 may influence host susceptibility to SARS-CoV-2 infection.

Competing Interest Statement

Donna Davies and Ratko Djukanovic are co-founders, shareholders and consultants to the University spin-out company, Synairgen, which is developing inhaled interferon-beta for treatment of respiratory viral infections, including SARS CoV2 (COVID-19).

Footnotes

  • ↵* Joint first authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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A novel isoform of ACE2 is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection
Cornelia Blume, Claire L Jackson, Cosma Mirella Spalluto, Jelmer Legebeke, Liliya Nazlamova, Franco Conforti, Jeanne-Marie Perotin-Collard, Martin Frank, Max Crispin, Janice Coles, James Thompson, Robert A Ridley, Lareb S N Dean, Matthew Loxham, Adnan Azim, Kamran Tariq, David Johnston, Paul J Skipp, Ratko Djukanovic, Diana Baralle, Chris McCormick, Donna E Davies, Jane S Lucas, Gabrielle Wheway, Vito Mennella
bioRxiv 2020.07.31.230870; doi: https://doi.org/10.1101/2020.07.31.230870
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A novel isoform of ACE2 is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection
Cornelia Blume, Claire L Jackson, Cosma Mirella Spalluto, Jelmer Legebeke, Liliya Nazlamova, Franco Conforti, Jeanne-Marie Perotin-Collard, Martin Frank, Max Crispin, Janice Coles, James Thompson, Robert A Ridley, Lareb S N Dean, Matthew Loxham, Adnan Azim, Kamran Tariq, David Johnston, Paul J Skipp, Ratko Djukanovic, Diana Baralle, Chris McCormick, Donna E Davies, Jane S Lucas, Gabrielle Wheway, Vito Mennella
bioRxiv 2020.07.31.230870; doi: https://doi.org/10.1101/2020.07.31.230870

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