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 B Fletcher, Diya Das, Kelly Street, Hector Roux de Bezieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W Logan, Bradley J Goldstein, Matthew S Grubb, John Ngai, Sandeep Robert Datta
Author Information
David H Brann: Harvard Medical School Department of Neurobiology, Boston MA 02115 USA. ORCID
Tatsuya Tsukahara: Harvard Medical School Department of Neurobiology, Boston MA 02115 USA. ORCID
Caleb Weinreb: Harvard Medical School Department of Neurobiology, Boston MA 02115 USA. ORCID
Marcela Lipovsek: Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London SE1 1UL, UK. ORCID
Koen Van den Berge: Department of Statistics, University of California, Berkeley, CA 94720.
Boying Gong: Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720.
Rebecca Chance: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720. ORCID
Iain C Macaulay: Earlham Institute, Norwich Research Park, Norwich, NR4 7UZ, UK. ORCID
Hsin-Jung Chou: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Russell B Fletcher: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Diya Das: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720. ORCID
Kelly Street: Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. ORCID
Hector Roux de Bezieux: Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720. ORCID
Yoon-Gi Choi: QB3 Functional Genomics Laboratory, University of California, Berkeley, CA 94720.
Davide Risso: Department of Statistical Sciences, University of Padova, Padova, Italy. ORCID
Sandrine Dudoit: Department of Statistics, University of California, Berkeley, CA 94720.
Elizabeth Purdom: Department of Statistics, University of California, Berkeley, CA 94720. ORCID
Jonathan Mill: University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter EX2 5DW, UK. ORCID
Ralph Abi Hachem: Duke University School of Medicine Department of Head and Neck Surgery & Communication Sciences, Durham, NC 27717 USA.
Hiroaki Matsunami: Duke University School of Medicine Department of Molecular Genetics and Microbiology, Department of Neurobiology, Duke Institute for Brain Sciences, Durham, NC 27717 US. ORCID
Darren W Logan: Waltham Petcare Science Institute, Leicestershire LE14 4RT, UK. ORCID
Bradley J Goldstein: Duke University School of Medicine Department of Head and Neck Surgery & Communication Sciences, Durham, NC 27717 USA. ORCID
Matthew S Grubb: Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London SE1 1UL, UK. ORCID
John Ngai: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720. ORCID
Sandeep Robert Datta: Harvard Medical School Department of Neurobiology, Boston MA 02115 USA. srdatta@hms.harvard.edu. ORCID
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.
