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Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue

Jennifer A. Aguiar, Benjamin J-M. Tremblay, Michael J. Mansfield, Owen Woody, Briallen Lobb, Arinjay Banerjee, Abiram Chandiramohan, Nicholas Tiessen, Anna Dvorkin-Gheva, Spencer Revill, Matthew S. Miller, Christopher Carlsten, Louise Organ, Chitra Joseph, Alison John, Paul Hanson, Bruce M. McManus, Gisli Jenkins, Karen Mossman, View ORCID ProfileKjetil Ask, Andrew C. Doxey, Jeremy A. Hirota
doi: https://doi.org/10.1101/2020.04.07.030742
Jennifer A. Aguiar
1Department of Biology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1
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Benjamin J-M. Tremblay
1Department of Biology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1
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Michael J. Mansfield
2Genomics and Regulatory Systems Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa, 904-0495, Japan
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Owen Woody
3Faculty of Mathematics, Waterloo, Waterloo, Ontario, Canada, N2L 3G1
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Briallen Lobb
1Department of Biology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1
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Arinjay Banerjee
4McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
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Abiram Chandiramohan
5Firestone Institute for Respiratory Health – Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 4A6
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Nicholas Tiessen
6Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
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Anna Dvorkin-Gheva
4McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
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Spencer Revill
5Firestone Institute for Respiratory Health – Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 4A6
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Matthew S. Miller
4McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
6Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
7Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
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Christopher Carlsten
8Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada, V6H 3Z6
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Louise Organ
9Nottingham NIHR Biomedical Research Centre, Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom, NG5 1PB
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Chitra Joseph
9Nottingham NIHR Biomedical Research Centre, Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom, NG5 1PB
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Alison John
9Nottingham NIHR Biomedical Research Centre, Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom, NG5 1PB
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Paul Hanson
10Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. V6Z 1Y6
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Bruce M. McManus
10Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. V6Z 1Y6
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Gisli Jenkins
9Nottingham NIHR Biomedical Research Centre, Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom, NG5 1PB
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Karen Mossman
4McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
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Kjetil Ask
4McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
5Firestone Institute for Respiratory Health – Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 4A6
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  • ORCID record for Kjetil Ask
Andrew C. Doxey
1Department of Biology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1
5Firestone Institute for Respiratory Health – Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 4A6
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  • For correspondence: hirotaja@mcmaster.ca acdoxey@uwaterloo.ca
Jeremy A. Hirota
1Department of Biology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1
4McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
5Firestone Institute for Respiratory Health – Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 4A6
6Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 4K1
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  • For correspondence: hirotaja@mcmaster.ca acdoxey@uwaterloo.ca
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ABSTRACT

In December 2019, SARS-CoV-2 emerged causing the COVID-19 pandemic. SARS-CoV, the agent responsible for the 2003 SARS outbreak, utilizes ACE2 and TMPRSS2 host molecules for viral entry. ACE2 and TMPRSS2 have recently been implicated in SARS-CoV-2 viral infection. Additional host molecules including ADAM17, cathepsin L, CD147, and GRP78 may also function as receptors for SARS-CoV-2.

To determine the expression and in situ localization of candidate SARS-CoV-2 receptors in the respiratory mucosa, we analyzed gene expression datasets from airway epithelial cells of 515 healthy subjects, gene promoter activity analysis using the FANTOM5 dataset containing 120 distinct sample types, single cell RNA sequencing (scRNAseq) of 10 healthy subjects, immunoblots on multiple airway epithelial cell types, and immunohistochemistry on 98 human lung samples.

We demonstrate absent to low ACE2 promoter activity in a variety of lung epithelial cell samples and low ACE2 gene expression in both microarray and scRNAseq datasets of epithelial cell populations. Consistent with gene expression, rare ACE2 protein expression was observed in the airway epithelium and alveoli of human lung. We present confirmatory evidence for the presence of TMPRSS2, CD147, and GRP78 protein in vitro in airway epithelial cells and confirm broad in situ protein expression of CD147 in the respiratory mucosa.

Collectively, our data suggest the presence of a mechanism dynamically regulating ACE2 expression in human lung, perhaps in periods of SARS-CoV-2 infection, and also suggest that alternate receptors for SARS-CoV-2 exist to facilitate initial host cell infection.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding: This work was supported by start-up funds from Hirota JA and a CIHR grant from Mossman K. Hirota JA is supported by the Canada Research Chairs program and an Ontario Early Researcher Award. Doxey AC is supported by NSERC and an Ontario Early Researcher Award.

  • This is the final version submitted for peer-review (European Respiratory Journal - ERJ). The version is double spaced as per ERJ submission guidelines. The final version now includes supplementary immunohistochemistry of human lung tissue microvasculature and human heart for positive ACE2 staining (previous version did not include this data). Paul Hanson and Bruce McManus were added as authors as they provided the human heart tissue for the ACE2 staining. A cartoon schematic was also added as a Figure 6 to summarize the characterization of the molecules.

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-ND 4.0 International license.
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Posted April 12, 2020.
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Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue
Jennifer A. Aguiar, Benjamin J-M. Tremblay, Michael J. Mansfield, Owen Woody, Briallen Lobb, Arinjay Banerjee, Abiram Chandiramohan, Nicholas Tiessen, Anna Dvorkin-Gheva, Spencer Revill, Matthew S. Miller, Christopher Carlsten, Louise Organ, Chitra Joseph, Alison John, Paul Hanson, Bruce M. McManus, Gisli Jenkins, Karen Mossman, Kjetil Ask, Andrew C. Doxey, Jeremy A. Hirota
bioRxiv 2020.04.07.030742; doi: https://doi.org/10.1101/2020.04.07.030742
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Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue
Jennifer A. Aguiar, Benjamin J-M. Tremblay, Michael J. Mansfield, Owen Woody, Briallen Lobb, Arinjay Banerjee, Abiram Chandiramohan, Nicholas Tiessen, Anna Dvorkin-Gheva, Spencer Revill, Matthew S. Miller, Christopher Carlsten, Louise Organ, Chitra Joseph, Alison John, Paul Hanson, Bruce M. McManus, Gisli Jenkins, Karen Mossman, Kjetil Ask, Andrew C. Doxey, Jeremy A. Hirota
bioRxiv 2020.04.07.030742; doi: https://doi.org/10.1101/2020.04.07.030742

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