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Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients

Jenny Meinhardt, Josefine Radke, Carsten Dittmayer, Ronja Mothes, Jonas Franz, Michael Laue, Julia Schneider, Sebastian Brünink, Olga Hassan, Werner Stenzel, Marc Windgassen, Larissa Rößler, Hans-Hilmar Goebel, Hubert Martin, Andreas Nitsche, Walter J. Schulz-Schaeffer, Samy Hakroush, Martin S. Winkler, Björn Tampe, Sefer Elezkurtaj, David Horst, Lars Oesterhelweg, Michael Tsokos, Barbara Ingold Heppner, Christine Stadelmann, Christian Drosten, Victor Max Corman, Helena Radbruch, Frank L. Heppner
doi: https://doi.org/10.1101/2020.06.04.135012
Jenny Meinhardt
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Josefine Radke
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
2Berlin Institute of Health (BIH), 10117 Berlin, Germany
3German Cancer Consortium (DKTK), Partner Site Berlin, CCCC (Campus Mitte), Invalidenstr. 80, 10115, Berlin, Germany
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Carsten Dittmayer
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Ronja Mothes
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Jonas Franz
4Institute of Neuropathology, University Medical Center, Göttingen, Germany
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Michael Laue
5Centre for Biological Threats and Special Pathogens (ZBS), Robert Koch Institute, Berlin, Germany
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Julia Schneider
6Department of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, and German Centre for Infection Research, 10117 Berlin, Germany
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Sebastian Brünink
6Department of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, and German Centre for Infection Research, 10117 Berlin, Germany
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Olga Hassan
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Werner Stenzel
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Marc Windgassen
7Institute of Forensic Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Larissa Rößler
7Institute of Forensic Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Hans-Hilmar Goebel
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Hubert Martin
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Andreas Nitsche
5Centre for Biological Threats and Special Pathogens (ZBS), Robert Koch Institute, Berlin, Germany
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Walter J. Schulz-Schaeffer
8Institute of Neuropathology, University of the Saarland, Kirrberger Str. 100, 66421 Homburg, Germany
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Samy Hakroush
9Institute of Pathology, University Medical Center Göttingen, Germany
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Martin S. Winkler
10Department of Anaesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Germany
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Björn Tampe
11Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany
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Sefer Elezkurtaj
12Institute of Pathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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David Horst
12Institute of Pathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Lars Oesterhelweg
7Institute of Forensic Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Michael Tsokos
7Institute of Forensic Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Barbara Ingold Heppner
12Institute of Pathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Christine Stadelmann
4Institute of Neuropathology, University Medical Center, Göttingen, Germany
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Christian Drosten
6Department of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, and German Centre for Infection Research, 10117 Berlin, Germany
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Victor Max Corman
6Department of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, and German Centre for Infection Research, 10117 Berlin, Germany
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Helena Radbruch
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Frank L. Heppner
1Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
2Berlin Institute of Health (BIH), 10117 Berlin, Germany
14Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany
15German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany
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  • For correspondence: frank.heppner@charite.de
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Abstract

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By precisely investigating and anatomically mapping oro- and pharyngeal regions and brains of 32 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# These authors jointly supervised this work

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients
Jenny Meinhardt, Josefine Radke, Carsten Dittmayer, Ronja Mothes, Jonas Franz, Michael Laue, Julia Schneider, Sebastian Brünink, Olga Hassan, Werner Stenzel, Marc Windgassen, Larissa Rößler, Hans-Hilmar Goebel, Hubert Martin, Andreas Nitsche, Walter J. Schulz-Schaeffer, Samy Hakroush, Martin S. Winkler, Björn Tampe, Sefer Elezkurtaj, David Horst, Lars Oesterhelweg, Michael Tsokos, Barbara Ingold Heppner, Christine Stadelmann, Christian Drosten, Victor Max Corman, Helena Radbruch, Frank L. Heppner
bioRxiv 2020.06.04.135012; doi: https://doi.org/10.1101/2020.06.04.135012
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Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients
Jenny Meinhardt, Josefine Radke, Carsten Dittmayer, Ronja Mothes, Jonas Franz, Michael Laue, Julia Schneider, Sebastian Brünink, Olga Hassan, Werner Stenzel, Marc Windgassen, Larissa Rößler, Hans-Hilmar Goebel, Hubert Martin, Andreas Nitsche, Walter J. Schulz-Schaeffer, Samy Hakroush, Martin S. Winkler, Björn Tampe, Sefer Elezkurtaj, David Horst, Lars Oesterhelweg, Michael Tsokos, Barbara Ingold Heppner, Christine Stadelmann, Christian Drosten, Victor Max Corman, Helena Radbruch, Frank L. Heppner
bioRxiv 2020.06.04.135012; doi: https://doi.org/10.1101/2020.06.04.135012

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