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

被引：929

作者：

Meinhardt, Jenny ^{[1
,2
,3
,4
]}

Radke, Josefine ^{[1
,2
,3
,4
,5
,6
]}

Dittmayer, Carsten ^{[1
,2
,3
,4
]}

Franz, Jonas ^{[7
,8
,9
]}

Thomas, Carolina ^{[7
,9
]}

Mothes, Ronja ^{[1
,2
,3
,4
]}

Laue, Michael ^{[10
]}

Schneider, Julia ^{[2
,3
,4
,11
,12
]}

Bruenink, Sebastian ^{[2
,3
,4
,11
,12
]}

Greuel, Selina ^{[2
,3
,4
,13
]}

Lehmann, Malte ^{[2
,3
,4
,14
]}

Hassan, Olga ^{[1
,2
,3
,4
]}

Aschman, Tom ^{[1
,2
,3
,4
]}

Schumann, Elisa ^{[1
,2
,3
,4
,6
]}

Chua, Robert Lorenz ^{[2
,3
,15
]}

Conrad, Christian ^{[2
,3
,15
]}

Eils, Roland ^{[2
,3
,15
,16
]}

Stenzel, Werner ^{[1
,2
,3
,4
]}

Windgassen, Marc ^{[2
,3
,4
,17
]}

Roessler, Larissa ^{[2
,3
,4
,17
]}

Goebel, Hans-Hilmar ^{[1
,2
,3
,4
]}

Gelderblom, Hans R. ^{[10
]}

Martin, Hubert ^{[1
,2
,3
,4
]}

Nitsche, Andreas ^{[10
]}

Schulz-Schaeffer, Walter J. ^{[18
]}

Hakroush, Samy ^{[19
]}

Winkler, Martin S. ^{[20
]}

Tampe, Bjoern ^{[21
]}

Scheibe, Franziska ^{[2
,3
,4
,22
,23
]}

Koertvelyessy, Peter ^{[2
,3
,4
,22
,24
]}

Reinhold, Dirk ^{[25
]}

Siegmund, Britta ^{[2
,3
,4
,14
]}

Kuehl, Anja A. ^{[2
,3
,4
,26
,27
]}

Elezkurtaj, Sefer ^{[2
,3
,4
,13
]}

Horst, David ^{[2
,3
,4
,13
]}

Oesterhelweg, Lars ^{[2
,3
,4
,17
]}

Tsokos, Michael ^{[2
,3
,4
,17
]}

Ingold-Heppner, Barbara ^{[28
]}

Stadelmann, Christine ^{[7
]}

Drosten, Christian ^{[2
,3
,4
,11
,12
]}

Corman, Victor Max ^{[2
,3
,4
,11
,12
]}

Radbruch, Helena ^{[1
,2
,3
,4
]}

Heppner, Frank L. ^{[1
,2
,3
,4
,5
,23
,29
]}

机构：

[1] Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany

[2] Free Univ Berlin, Berlin, Germany

[3] Humboldt Univ, Berlin, Germany

[4] Berlin Inst Hlth, Berlin, Germany

[5] Berlin Inst Hlth BIH, Berlin, Germany

[6] German Canc Consortium DKTK, Partner Site Berlin, CCCC Campus Mitte, Berlin, Germany

[7] Univ Med Ctr, Inst Neuropathol, Gottingen, Germany

[8] Univ Gottingen, Campus Inst Dynam Biol Networks, Gottingen, Germany

[9] Max Planck Inst Expt Med, Gottingen, Germany

[10] Robert Koch Inst, Ctr Biol Threats & Special Pathogens ZBS, Berlin, Germany

[11] Charite Univ Med Berlin, Inst Virol, Berlin, Germany

[12] German Ctr Infect Res, Berlin, Germany

[13] Charite Univ Med Berlin, Inst Pathol, Berlin, Germany

[14] Charite Univ Med Berlin, Div Gastroenterol Infectiol & Rheumatol, Med Dept, Berlin, Germany

[15] Berlin Inst Hlth BIH, Ctr Digital Hlth, Berlin, Germany

[16] Heidelberg Univ, Fac Med, Hlth Data Sci Unit, Heidelberg, Germany

[17] Charite Univ Med Berlin, Inst Legal Med & Forens Sci, Berlin, Germany

[18] Univ Saarland, Inst Neuropathol, Homburg, Germany

[19] Univ Med Ctr Gottingen, Inst Pathol, Gottingen, Germany

[20] Univ Med Ctr Gottingen, Dept Anaesthesiol & Intens Care Med, Gottingen, Germany

[21] Univ Med Ctr Gottingen, Dept Nephrol & Rheumatol, Gottingen, Germany

[22] Charite Univ Med Berlin, Dept Neurol, Berlin, Germany

[23] NeuroCure, Cluster Excellence, Berlin, Germany

[24] German Ctr Neurodegenerat Dis DZNE, Magdeburg, Germany

[25] Otto von Guericke Univ, Inst Mol & Clin Immunol, Magdeburg, Germany

[26] Charite Univ Med Berlin, Berlin, Germany

[27] iPATH Berlin, Berlin, Germany

[28] DRK Klin Berlin, Inst Pathol, Berlin, Germany

[29] German Ctr Neurodegenerat Dis DZNE Berlin, Berlin, Germany

来源：

NATURE NEUROSCIENCE | 2021年 / 24卷 / 02期

关键词：

INFECTION;

D O I：

10.1038/s41593-020-00758-5

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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. The authors demonstrate the presence of SARS-CoV-2 in the nasopharynx and brain, suggesting that the virus is present in the CNS and may enter through the olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue.

引用

页码：168 / 175

页数：8

共 48 条

[1] Neuroinvasion by human respiratory coronaviruses
Arbour, N
Day, R
Newcombe, J
Talbot, PJ
[J]. JOURNAL OF VIROLOGY, 2000, 74 (19) : 8913 - 8921
[2] Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms
Baig, Abdul Mannan
Khaleeq, Areeba
Ali, Usman
Syeda, Hira
[J]. ACS CHEMICAL NEUROSCIENCE, 2020, 11 (07): : 995 - 998
[3] Besson Sebastien, 2019, Digit Pathol (2019), V2019, P3, DOI 10.1007/978-3-030-23937-4_1
[4] Virus-induced double-membrane vesicles
Blanchard, Emmanuelle
Roingeard, Philippe
[J]. CELLULAR MICROBIOLOGY, 2015, 17 (01) : 45 - 50
[5] 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
[J]. SCIENCE ADVANCES, 2020, 6 (31)
[6] SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection
Butowt, Rafal
Bilinska, Katarzyna
[J]. ACS CHEMICAL NEUROSCIENCE, 2020, 11 (09): : 1200 - 1203
[7] Olfactory horizontal basal cells demonstrate a conserved multipotent progenitor phenotype
Carter, LA
MacDonald, JL
Roskams, AJ
[J]. JOURNAL OF NEUROSCIENCE, 2004, 24 (25) : 5670 - 5683
[8] Cevik Lokman, 2020, Free Neuropathol, V1, DOI 10.17879/freeneuropathology-2020-2736
[9] Neurotropism of SARS-CoV 2: Mechanisms and manifestations
Conde Cardona, Giancarlos
Quintana Pajaro, Loraine D.
Quintero Marzola, Ivan D.
Ramos Villegas, Yancarlos
Moscote Salazar, Luis R.
[J]. JOURNAL OF THE NEUROLOGICAL SCIENCES, 2020, 412
[10] Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR (Publication with Expression of Concern)
Corman, Victor M.
Landt, Olfert
Kaiser, Marco
Molenkamp, Richard
Meijer, Adam
Chu, Daniel K. W.
Bleicker, Tobias
Bruenink, Sebastian
Schneider, Julia
Schmidt, Marie Luisa
Mulders, Daphne G. J. C.
Haagmans, Bart L.
van der Veer, Bas
van den Brink, Sharon
Wijsman, Lisa
Goderski, Gabriel
Romette, Jean-Louis
Ellis, Joanna
Zambon, Maria
Peiris, Malik
Goossens, Herman
Reusken, Chantal
Koopmans, Marion P. G.
Drosten, Christian
[J]. EUROSURVEILLANCE, 2020, 25 (03) : 23 - 30

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