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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
10Berkeley Institute for Data Science, University of California, Berkeley
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Kelly Street
11Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA
12Department 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
13Center for Computational Biology, University of California, Berkeley, CA 94720
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Yoon-Gi Choi
14QB3 Functional Genomics Laboratory, University of California, Berkeley, CA 94720
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Davide Risso
15Department 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
16University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter EX2 5DW, UK16
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Ralph Abi Hachem
17Duke University School of Medicine Department of Head and Neck Surgery & Communication Sciences, Durham, NC 27717 USA
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Hiroaki Matsunami
18Duke 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
19Waltham Petcare Science Institute, Leicestershire LE14 4RT, UK
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Bradley J. Goldstein
17Duke 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
14QB3 Functional Genomics Laboratory, University of California, Berkeley, CA 94720
20Helen 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

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) – the causal agent in COVID-19 – affects olfaction directly by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing revealed that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing and immunostaining demonstrated ACE2 expression in support cells, stem cells, and perivascular cells; in contrast, neurons in both the olfactory epithelium and bulb did not express ACE2 message or protein. 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.

Competing Interest Statement

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

Footnotes

  • now includes new DropSeq dataset, new human olfactory epithelium staining, new mouse olfactory epithelium and bulb staining

  • 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 May 18, 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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