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

Julia A. Schneider; Walter Schulz‐Schaeffer; Jonas Franz; Roland Eils; Christian Drosten; Helena Radbruch; Britta Siegmund; Christine Stadelmann; Frank L. Heppner; Christian Conrad; Hans‐Hilmar Goebel; Werner Stenzel; Victor M. Corman; David A. Horst; Anja Andrea Kühl; Ronja Mothes; Josefine Radke; Jenny Meinhardt; Tom Aschman; Robert Lorenz Chua; Carolina Thomas; Elisa Schumann; Péter Körtvelyessy; Dirk Reinhold; Sefer Elezkurtaj; Andreas Nitsche; Sebastian Brünink; Michael M. Laue; Franziska Scheibe; Martin Sebastian Winkler; Carsten Dittmayer; Michael Tsokos; Selina Greuel; Malte Lehmann; Olga Hassan; Marc Windgassen; Larissa Rößler; Hans R. Gelderblom; Hubert Martin; Samy Hakroush; Björn Tampe; Lars Oesterhelweg; Barbara Ingold‐Heppner

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

Трансмукозное проникновение SARS-CoV-2 через обонятельную слизистую как путь проникновения в центральную нервную систему у лиц с COVID-19

Julia A. Schneider, Walter Schulz‐Schaeffer, Jonas Franz, Roland Eils, Christian Drosten, Helena Radbruch, Britta Siegmund, Christine Stadelmann, Frank L. Heppner, Christian Conrad, Hans‐Hilmar Goebel, Werner Stenzel, Victor M. Corman, David A. Horst, Anja Andrea Kühl, Ronja Mothes, Josefine Radke, Jenny Meinhardt, Tom Aschman, Robert Lorenz Chua, Carolina Thomas, Elisa Schumann, Péter Körtvelyessy, Dirk Reinhold, Sefer Elezkurtaj, Andreas Nitsche, Sebastian Brünink, Michael M. Laue, Franziska Scheibe, Martin Sebastian Winkler, Carsten Dittmayer, Michael Tsokos, Selina Greuel, Malte Lehmann, Olga Hassan, Marc Windgassen, Larissa Rößler, Hans R. Gelderblom, Hubert Martin, Samy Hakroush, Björn Tampe, Lars Oesterhelweg, Barbara Ingold‐Heppner

2020-11-30

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SARS-CoV-2 neurotropismcentral nervous system invasionneural–mucosal interfaceolfactory mucosathromboembolic ischemic infarction

Abstract (AI)

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.

Key Findings

After olfactory entry, SARS-CoV-2 appears to follow neuroanatomical pathways and reach areas including the medulla oblongata’s primary respiratory and cardiovascular control center.

SARS-CoV-2 RNA and protein were detected in anatomically distinct regions of the nasopharynx and brain in individuals with COVID-19.

SARS-CoV-2 may enter the CNS by crossing the olfactory neural–mucosal interface, exploiting the proximity of olfactory mucosal, endothelial, and nervous tissues.

The findings provide evidence of SARS-CoV-2 neurotropism and CNS involvement, including thromboembolic ischemic infarction-associated morphological changes.

Research Object

SARS-CoV-2 infection of the olfactory mucosa, nasopharynx, and central nervous system in individuals with COVID-19

Research Subject

Olfactory transmucosal neuroinvasion, neurotropism, and associated CNS morphological changes including thromboembolic ischemic infarction

Publication Details

DOI

10.1038/s41593-020-00758-5

Publication Date

2020-11-30

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ISSN

Cited by

1458

Open access PDF

https://www.nature.com/articles/s41593-020-0075…

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Author Information

Authors

Julia A. Schneider

Walter Schulz‐Schaeffer

Jonas Franz

Roland Eils

Christian Drosten

Helena Radbruch

Britta Siegmund

Christine Stadelmann

Frank L. Heppner

Christian Conrad

Hans‐Hilmar Goebel

Werner Stenzel

Victor M. Corman

David A. Horst

Anja Andrea Kühl

Ronja Mothes

Josefine Radke

Jenny Meinhardt

Tom Aschman

Robert Lorenz Chua

Carolina Thomas

Elisa Schumann

Péter Körtvelyessy

Dirk Reinhold

Sefer Elezkurtaj

Andreas Nitsche

Sebastian Brünink

Michael M. Laue

Franziska Scheibe

Martin Sebastian Winkler

Carsten Dittmayer

Michael Tsokos

Selina Greuel

Malte Lehmann

Olga Hassan

Marc Windgassen

Larissa Rößler

Hans R. Gelderblom

Hubert Martin

Samy Hakroush

Björn Tampe

Lars Oesterhelweg

Barbara Ingold‐Heppner

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References available in scid.ai8

Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR2020 Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China2020 Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19)2020 A first case of meningitis/encephalitis associated with SARS-Coronavirus-22020 Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia2020 Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study2020 Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology2020 Central nervous system involvement by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)2020

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