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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

View ORCID ProfileDavid H. Brann, View ORCID ProfileTatsuya Tsukahara, View ORCID ProfileCaleb Weinreb, Marcela Lipovsek, View ORCID ProfileKoen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, View ORCID ProfileDiya Das, View ORCID ProfileKelly Street, View ORCID ProfileHector Roux de Bezieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, View ORCID ProfileElizabeth Purdom, Jonathan S. Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W. Logan, Bradley J. Goldstein, Matthew S. Grubb, John Ngai, View ORCID ProfileSandeep Robert Datta
doi: https://doi.org/10.1101/2020.03.25.009084
David H. Brann
1Harvard Medical School Department of Neurobiology, Boston MA 02115 USA
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Tatsuya Tsukahara
1Harvard Medical School Department of Neurobiology, Boston MA 02115 USA
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Caleb Weinreb
1Harvard Medical School Department of Neurobiology, Boston MA 02115 USA
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Marcela Lipovsek
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London SE1 1UL, UK
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Koen Van den Berge
3Department of Statistics, University of California, Berkeley, CA 94720
4Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
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Boying Gong
5Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720
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Rebecca Chance
6Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
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Iain C. Macaulay
7Earlham Institute, Norwich Research Park, Norwich, NR4 7UZ, UK
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Hsin-jung Chou
6Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
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Russell Fletcher
6Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
8Surrozen, Inc., South San Francisco, CA 94080
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Diya Das
6Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
9Genentech, Inc., South San Francisco, CA 94080
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Kelly Street
10Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA
11Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
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Hector Roux de Bezieux
5Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720
12Center for Computational Biology, University of California, Berkeley, CA 94720
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Yoon-Gi Choi
13QB3 Functional Genomics Laboratory, University of California, Berkeley, CA 94720
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Davide Risso
14Department of Statistical Sciences, University of Padova, Padova, Italy
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Sandrine Dudoit
3Department of Statistics, University of California, Berkeley, CA 94720
5Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720
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Elizabeth Purdom
5Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720
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Jonathan S. Mill
15University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter EX2 5DW, UK16
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Ralph Abi Hachem
16Duke University School of Medicine Department of Head and Neck Surgery & Communication Sciences, Durham, NC 27717 USA
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Hiroaki Matsunami
17Duke University School of Medicine Department of Molecular Genetics and Microbiology, Department of Neurobiology, Duke Institute for Brain Sciences, Durham, NC 27717 US
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Darren W. Logan
18Waltham Petcare Science Institute, Leicestershire LE14 4RT, UK
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Bradley J. Goldstein
16Duke University School of Medicine Department of Head and Neck Surgery & Communication Sciences, Durham, NC 27717 USA
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Matthew S. Grubb
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London SE1 1UL, UK
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John Ngai
6Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
13QB3 Functional Genomics Laboratory, University of California, Berkeley, CA 94720
19Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720
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Sandeep Robert Datta
1Harvard Medical School Department of Neurobiology, Boston MA 02115 USA
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  • For correspondence: srdatta@hms.harvard.edu
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Abstract

A subset of COVID-19 patients exhibit altered olfactory function. Here we analyze bulk and single cell RNA-Seq datasets to identify cell types in the olfactory epithelium and olfactory bulb that express cell entry molecules that mediate infection by SARS-CoV-2 (CoV-2), the causal agent in COVID-19. We find that samples from whole olfactory mucosa in species including mouse and human express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, neither olfactory sensory neurons nor olfactory bulb neurons express these genes, which are instead expressed in support cells, stem cells, and perivascular cells. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.

One Sentence Summary Analysis of new and previously published single-cell sequencing datasets reveals that the SARS-CoV2 receptor ACE2 is expressed in olfactory support cells, stem cells and perivascular cells — but not in neurons — suggesting mechanisms through which the COVID-19 syndrome could lead to olfactory dysfunction.

Competing Interest Statement

DL is an employee of Mars, Inc. None of the other authors have competing interests to declare.

Footnotes

  • Includes previously unpublished datasets (whole olfactory mucosa scSeq, HBC scSeq, olfactory bulb scSeq, olfactory bulb dopaminergic neuron deep sequencing), ACE2 immunohistochemistry in human tissue, and analysis of SARS-CoV-2 cell entry genes in the olfactory bulb and brain; research groups of John Ngai, Matthew Grubb, Bradley Goldstein, Hiro Matsunami (and colleagues) added as collaborators.

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680959/bin/srep18178-s2.xls

  • https://doi.org/10.1371/journal.pone.0113170.s014

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52464

  • https://advances.sciencemag.org/highwire/filestream/217162/field_highwire_adjunct_files/0/aax0396_Data_file_S1.xlsx

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139522

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99251

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120199

  • https://www.genomique.eu/cellbrowser/HCA/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 09, 2020.
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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bezieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan S. Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W. Logan, Bradley J. Goldstein, Matthew S. Grubb, John Ngai, Sandeep Robert Datta
bioRxiv 2020.03.25.009084; doi: https://doi.org/10.1101/2020.03.25.009084
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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bezieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan S. Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W. Logan, Bradley J. Goldstein, Matthew S. Grubb, John Ngai, Sandeep Robert Datta
bioRxiv 2020.03.25.009084; doi: https://doi.org/10.1101/2020.03.25.009084

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