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
Altered olfactory function is a common symptom of COVID-19 (coronavirus disease 2019), but its etiology is unknown. A key question is whether SARS-CoV-2 (severe acute respiratory syndrome coronavirus 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, by perturbing support cells. Bulk and single-cell RNA sequencing revealed that support and stem cells in the human and mouse olfactory epithelium and vascular pericytes in the mouse olfactory bulb express angiotensin-converting enzyme 2 (ACE2), which is essential for CoV-2 cell entry. In contrast, ACE2 was not detected in either olfactory sensory neurons or olfactory bulb neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally located olfactory epithelial sustentacular cells and mouse olfactory bulb pericytes. These findings suggest that CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in patients with COVID-19.
abc5801
Science Advances
https://doi.org/10.1126/sciadv.abc5801
10.1126/sciadv.abc5801Licence: CC BY
Brann, D. H., Tsukahara, T., Weinreb, C., Lipovsek, M., Van Den Berge, K., Gong, B., Chance, R., Macaulay, I. C., Chou, H. J., Fletcher, R. B., Das, D., Street, K., De Bezieux, H. R., Choi, Y. G., Risso, D., Dudoit, S., Purdom, E., Mill, J., Hachem, R. A., ... Datta, S. R. (2020). Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science Advances, 6(31), [abc5801]. https://doi.org/10.1126/sciadv.abc5801
Brann, David H. ; Tsukahara, Tatsuya ; Weinreb, Caleb ; Lipovsek, Marcela ; Van Den Berge, Koen ; Gong, Boying ; Chance, Rebecca ; Macaulay, Iain C. ; Chou, Hsin Jung ; Fletcher, Russell B. ; Das, Diya ; Street, Kelly ; De Bezieux, Hector Roux ; Choi, Yoon Gi ; Risso, Davide ; Dudoit, Sandrine ; Purdom, Elizabeth ; Mill, Jonathan ; Hachem, Ralph Abi ; Matsunami, Hiroaki ; Logan, Darren W. ; Goldstein, Bradley J. ; Grubb, Matthew S. ; Ngai, John ; Datta, Sandeep Robert. / Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. In: Science Advances. 2020 ; Vol. 6, No. 31.
@article{cd8cef55724b482eb244be87f2e64d1a,
title = "Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia",
abstract = "Altered olfactory function is a common symptom of COVID-19 (coronavirus disease 2019), but its etiology is unknown. A key question is whether SARS-CoV-2 (severe acute respiratory syndrome coronavirus 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, by perturbing support cells. Bulk and single-cell RNA sequencing revealed that support and stem cells in the human and mouse olfactory epithelium and vascular pericytes in the mouse olfactory bulb express angiotensin-converting enzyme 2 (ACE2), which is essential for CoV-2 cell entry. In contrast, ACE2 was not detected in either olfactory sensory neurons or olfactory bulb neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally located olfactory epithelial sustentacular cells and mouse olfactory bulb pericytes. These findings suggest that CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in patients with COVID-19.",
author = "Brann, {David H.} and Tatsuya Tsukahara and Caleb Weinreb and Marcela Lipovsek and {Van Den Berge}, Koen and Boying Gong and Rebecca Chance and Macaulay, {Iain C.} and Chou, {Hsin Jung} and Fletcher, {Russell B.} and Diya Das and Kelly Street and {De Bezieux}, {Hector Roux} and Choi, {Yoon Gi} and Davide Risso and Sandrine Dudoit and Elizabeth Purdom and Jonathan Mill and Hachem, {Ralph Abi} and Hiroaki Matsunami and Logan, {Darren W.} and Goldstein, {Bradley J.} and Grubb, {Matthew S.} and John Ngai and Datta, {Sandeep Robert}",
note = "Funding Information: S.R.D. was supported by grants RO11DC016222 and U19 NS112953 from the NIH and by the Simons Collaboration on the Global Brain, and the HMS Neurobiology Imaging Facility was supported by NIH grant P30NS072030. D.H.B. was supported by an NSF Graduate Research Fellowship. J.N. was supported by NIH grant RO1DC007235. D.R. was supported by Programma per Giovani Ricercatori Rita Levi Montalcini granted by the Italian Ministry of Education, University, and Research. K.V.d.B. is a postdoctoral fellow of the Belgian American Educational Foundation (BAEF) and was supported by the Research Foundation Flanders (FWO), grant 1246220N. D.D. was a fellow of the Berkeley Institute for Data Science, funded in part by the Gordon and Betty Moore Foundation (grant GBMF3834) and the Alfred P. Sloan Foundation (grant 2013-10-27). M.L. and M.S.G. were supported by a Leverhulme Trust Research Grant (RPG-2016-095) and a Consolidator Grant from the European Research Council (725729; FUNCOPLAN). J.M. was supported by a Medical Research Council grant (K013807) and a Medical Research Council Clinical Infrastructure Award (M008924). I.C.M. was supported by a BBSRC New Investigator Grant (BB/P022073/1) and the BBSRC National Capability in Genomics and Single Cell Analysis at Earlham Institute (BB/CCG1720/1). B.J.G. was supported by grant R01DC016859. H.M. was supported by grants R01DC014423 and R01DC016224. Publisher Copyright: {\textcopyright} 2020 The Authors.",
doi = "10.1126/sciadv.abc5801",
journal = "Science Advances",
publisher = "American Association for the Advancement of Science",
Brann, DH, Tsukahara, T, Weinreb, C, Lipovsek, M, Van Den Berge, K, Gong, B, Chance, R, Macaulay, IC, Chou, HJ, Fletcher, RB, Das, D, Street, K, De Bezieux, HR, Choi, YG, Risso, D, Dudoit, S, Purdom, E, Mill, J, Hachem, RA, Matsunami, H, Logan, DW, Goldstein, BJ, Grubb, MS, Ngai, J & Datta, SR 2020, 'Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia', Science Advances, vol. 6, no. 31, abc5801. https://doi.org/10.1126/sciadv.abc5801
Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. / Brann, David H.; Tsukahara, Tatsuya; Weinreb, Caleb; Lipovsek, Marcela; Van Den Berge, Koen; Gong, Boying; Chance, Rebecca; Macaulay, Iain C.; Chou, Hsin Jung; Fletcher, Russell B.; Das, Diya; Street, Kelly; De Bezieux, Hector Roux; Choi, Yoon Gi; Risso, Davide; Dudoit, Sandrine; Purdom, Elizabeth; Mill, Jonathan; Hachem, Ralph Abi; Matsunami, Hiroaki; Logan, Darren W.; Goldstein, Bradley J.; Grubb, Matthew S.; Ngai, John; Datta, Sandeep Robert.
In: Science Advances, Vol. 6, No. 31, abc5801, 07.2020.
T1 - Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
AU - Brann, David H.
AU - Tsukahara, Tatsuya
AU - Weinreb, Caleb
AU - Lipovsek, Marcela
AU - Van Den Berge, Koen
AU - Gong, Boying
AU - Chance, Rebecca
AU - Macaulay, Iain C.
AU - Chou, Hsin Jung
AU - Fletcher, Russell B.
AU - Das, Diya
AU - Street, Kelly
AU - De Bezieux, Hector Roux
AU - Choi, Yoon Gi
AU - Risso, Davide
AU - Dudoit, Sandrine
AU - Purdom, Elizabeth
AU - Mill, Jonathan
AU - Hachem, Ralph Abi
AU - Matsunami, Hiroaki
AU - Logan, Darren W.
AU - Goldstein, Bradley J.
AU - Grubb, Matthew S.
AU - Ngai, John
AU - Datta, Sandeep Robert
N1 - Funding Information: S.R.D. was supported by grants RO11DC016222 and U19 NS112953 from the NIH and by the Simons Collaboration on the Global Brain, and the HMS Neurobiology Imaging Facility was supported by NIH grant P30NS072030. D.H.B. was supported by an NSF Graduate Research Fellowship. J.N. was supported by NIH grant RO1DC007235. D.R. was supported by Programma per Giovani Ricercatori Rita Levi Montalcini granted by the Italian Ministry of Education, University, and Research. K.V.d.B. is a postdoctoral fellow of the Belgian American Educational Foundation (BAEF) and was supported by the Research Foundation Flanders (FWO), grant 1246220N. D.D. was a fellow of the Berkeley Institute for Data Science, funded in part by the Gordon and Betty Moore Foundation (grant GBMF3834) and the Alfred P. Sloan Foundation (grant 2013-10-27). M.L. and M.S.G. were supported by a Leverhulme Trust Research Grant (RPG-2016-095) and a Consolidator Grant from the European Research Council (725729; FUNCOPLAN). J.M. was supported by a Medical Research Council grant (K013807) and a Medical Research Council Clinical Infrastructure Award (M008924). I.C.M. was supported by a BBSRC New Investigator Grant (BB/P022073/1) and the BBSRC National Capability in Genomics and Single Cell Analysis at Earlham Institute (BB/CCG1720/1). B.J.G. was supported by grant R01DC016859. H.M. was supported by grants R01DC014423 and R01DC016224. Publisher Copyright: © 2020 The Authors.
N2 - Altered olfactory function is a common symptom of COVID-19 (coronavirus disease 2019), but its etiology is unknown. A key question is whether SARS-CoV-2 (severe acute respiratory syndrome coronavirus 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, by perturbing support cells. Bulk and single-cell RNA sequencing revealed that support and stem cells in the human and mouse olfactory epithelium and vascular pericytes in the mouse olfactory bulb express angiotensin-converting enzyme 2 (ACE2), which is essential for CoV-2 cell entry. In contrast, ACE2 was not detected in either olfactory sensory neurons or olfactory bulb neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally located olfactory epithelial sustentacular cells and mouse olfactory bulb pericytes. These findings suggest that CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in patients with COVID-19.
AB - Altered olfactory function is a common symptom of COVID-19 (coronavirus disease 2019), but its etiology is unknown. A key question is whether SARS-CoV-2 (severe acute respiratory syndrome coronavirus 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, by perturbing support cells. Bulk and single-cell RNA sequencing revealed that support and stem cells in the human and mouse olfactory epithelium and vascular pericytes in the mouse olfactory bulb express angiotensin-converting enzyme 2 (ACE2), which is essential for CoV-2 cell entry. In contrast, ACE2 was not detected in either olfactory sensory neurons or olfactory bulb neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally located olfactory epithelial sustentacular cells and mouse olfactory bulb pericytes. These findings suggest that CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in patients with COVID-19.
U2 - 10.1126/sciadv.abc5801
DO - 10.1126/sciadv.abc5801
JO - Science Advances
JF - Science Advances
M1 - abc5801
Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van Den Berge K, Gong B et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science Advances. 2020 Jul;6(31). abc5801. https://doi.org/10.1126/sciadv.abc5801