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

Author:

Brann David H.1ORCID,Tsukahara Tatsuya1ORCID,Weinreb Caleb1ORCID,Lipovsek Marcela2ORCID,Van den Berge Koen34,Gong Boying5,Chance Rebecca6ORCID,Macaulay Iain C.7ORCID,Chou Hsin-Jung6,Fletcher Russell B.68,Das Diya6910ORCID,Street Kelly1112ORCID,de Bezieux Hector Roux513ORCID,Choi Yoon-Gi14,Risso Davide15ORCID,Dudoit Sandrine35,Purdom Elizabeth3ORCID,Mill Jonathan16ORCID,Hachem Ralph Abi17,Matsunami Hiroaki18ORCID,Logan Darren W.19ORCID,Goldstein Bradley J.17ORCID,Grubb Matthew S.2ORCID,Ngai John6142021ORCID,Datta Sandeep Robert1ORCID

Affiliation:

1. Harvard Medical School Department of Neurobiology, Boston MA 02115 USA.

2. Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London SE1 1UL, UK

3. Department of Statistics, University of California, Berkeley, CA 94720

4. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium

5. Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720

6. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

7. Earlham Institute, Norwich Research Park, Norwich, NR4 7UZ, UK

8. Present address: Surrozen, Inc., South San Francisco, CA 94080

9. Berkeley Institute for Data Science, University of California, Berkeley

10. Present address: Genentech, Inc., South San Francisco, CA 94080

11. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA

12. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA

13. Center for Computational Biology, University of California, Berkeley, CA 94720

14. QB3 Functional Genomics Laboratory, University of California, Berkeley, CA 94720

15. Department of Statistical Sciences, University of Padova, Padova, Italy

16. University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter EX2 5DW, UK

17. Duke University School of Medicine Department of Head and Neck Surgery & Communication Sciences, Durham, NC 27717 USA.

18. Duke University School of Medicine Department of Molecular Genetics and Microbiology, Department of Neurobiology, Duke Institute for Brain Sciences, Durham, NC 27717 US

19. Waltham Petcare Science Institute, Leicestershire LE14 4RT, UK.

20. Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720

21. Present address: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD

Abstract

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 demonstrated 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 revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. 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.

Funder

National Institutes of Health

Leverhulme Trust

European Research Council

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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