Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

Jenny Meinhardt^#¹, Josefine Radke^#^{1

2

3}, Carsten Dittmayer^#¹, Jonas Franz^{4

5

6}, Carolina Thomas^{4

6}, Ronja Mothes¹, Michael Laue⁷, Julia Schneider⁸, Sebastian Brünink⁸, Selina Greuel⁹, Malte Lehmann¹⁰, Olga Hassan¹, Tom Aschman¹, Elisa Schumann^{1

3}, Robert Lorenz Chua¹¹, Christian Conrad¹¹, Roland Eils^{11

12}, Werner Stenzel¹, Marc Windgassen¹³, Larissa Rößler¹³, Hans-Hilmar Goebel¹, Hans R Gelderblom⁷, Hubert Martin¹, Andreas Nitsche⁷, Walter J Schulz-Schaeffer¹⁴, Samy Hakroush¹⁵, Martin S Winkler¹⁶, Björn Tampe¹⁷, Franziska Scheibe^{18

19}, Péter Körtvélyessy^{18

20}, Dirk Reinhold²¹, Britta Siegmund¹⁰, Anja A Kühl²², Sefer Elezkurtaj⁹, David Horst⁹, Lars Oesterhelweg¹³, Michael Tsokos¹³, Barbara Ingold-Heppner²³, Christine Stadelmann⁴, Christian Drosten⁸, Victor Max Corman⁸, Helena Radbruch¹, Frank L Heppner^{24

25

26

27}

Affiliations

¹ Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
² Berlin Institute of Health (BIH), Berlin, Germany.
³ German Cancer Consortium (DKTK), Partner Site Berlin, CCCC (Campus Mitte), Berlin, Germany.
⁴ Institute of Neuropathology, University Medical Center, Göttingen, Germany.
⁵ Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany.
⁶ Max Planck Institute for Experimental Medicine, Göttingen, Germany.
⁷ Centre for Biological Threats and Special Pathogens (ZBS), Robert Koch Institute, Berlin, Germany.
⁸ Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and German Centre for Infection Research, Berlin, Germany.
⁹ Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹⁰ Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹¹ Center for Digital Health, Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹² Health Data Science Unit, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
¹³ Institute of Legal Medicine and Forensic Sciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹⁴ Institute of Neuropathology, University of the Saarland, Homburg, Germany.
¹⁵ Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
¹⁶ Department of Anaesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany.
¹⁷ Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.
¹⁸ Department of Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹⁹ Cluster of Excellence, NeuroCure, Berlin, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
²¹ Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
²² Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, and iPATH.Berlin, Berlin, Germany.
²³ Institute of Pathology, DRK Kliniken Berlin, Berlin, Germany.
²⁴ Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. frank.heppner@charite.de.
²⁵ Berlin Institute of Health (BIH), Berlin, Germany. frank.heppner@charite.de.
²⁶ Cluster of Excellence, NeuroCure, Berlin, Germany. frank.heppner@charite.de.
²⁷ German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany. frank.heppner@charite.de.

^# Contributed equally.

PMID: 33257876
DOI: 10.1038/s41593-020-00758-5

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

Jenny Meinhardt et al. Nat Neurosci. 2021 Feb.

. 2021 Feb;24(2):168-175.

doi: 10.1038/s41593-020-00758-5. Epub 2020 Nov 30.

Authors

Affiliations

¹ Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
² Berlin Institute of Health (BIH), Berlin, Germany.
³ German Cancer Consortium (DKTK), Partner Site Berlin, CCCC (Campus Mitte), Berlin, Germany.
⁴ Institute of Neuropathology, University Medical Center, Göttingen, Germany.
⁵ Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany.
⁶ Max Planck Institute for Experimental Medicine, Göttingen, Germany.
⁷ Centre for Biological Threats and Special Pathogens (ZBS), Robert Koch Institute, Berlin, Germany.
⁸ Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and German Centre for Infection Research, Berlin, Germany.
⁹ Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹⁰ Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹¹ Center for Digital Health, Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹² Health Data Science Unit, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
¹³ Institute of Legal Medicine and Forensic Sciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹⁴ Institute of Neuropathology, University of the Saarland, Homburg, Germany.
¹⁵ Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
¹⁶ Department of Anaesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany.
¹⁷ Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.
¹⁸ Department of Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
¹⁹ Cluster of Excellence, NeuroCure, Berlin, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
²¹ Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
²² Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, and iPATH.Berlin, Berlin, Germany.
²³ Institute of Pathology, DRK Kliniken Berlin, Berlin, Germany.
²⁴ Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. frank.heppner@charite.de.
²⁵ Berlin Institute of Health (BIH), Berlin, Germany. frank.heppner@charite.de.
²⁶ Cluster of Excellence, NeuroCure, Berlin, Germany. frank.heppner@charite.de.
²⁷ German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany. frank.heppner@charite.de.

^# Contributed equally.

PMID: 33257876
DOI: 10.1038/s41593-020-00758-5

Abstract

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.

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Comment in

SARS-CoV-2 detected in olfactory neurons.
Lemprière S. Lemprière S. Nat Rev Neurol. 2021 Feb;17(2):63. doi: 10.1038/s41582-020-00449-6. Nat Rev Neurol. 2021. PMID: 33398125 Free PMC article. No abstract available.
A CNS gateway for SARS-CoV-2.
Yates D. Yates D. Nat Rev Neurosci. 2021 Feb;22(2):74-75. doi: 10.1038/s41583-020-00427-3. Nat Rev Neurosci. 2021. PMID: 33398138 Free PMC article.

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Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

Affiliations

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

Authors

Affiliations

Abstract

Comment in

References

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LinkOut - more resources

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Medical

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