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

[21] Immunohistochemical Characterization of Human Olfactory Tissue
Holbrook, Eric H.
Wu, Enming
Curry, William T.
Lin, Derrick T.
Schwob, James E.
[J]. LARYNGOSCOPE, 2011, 121 (08) : 1687 - 1701
[22] Huang CL, 2020, LANCET, V395, P497, DOI [10.1016/S0140-6736(20)30211-7, 10.1016/S0140-6736(20)30183-5]
[23] Neuropathological findings in two patients with fatal COVID-19
Jensen, M. P.
Le Quesne, J.
Officer-Jones, L.
Teodosio, A.
Thaventhiran, J.
Ficken, C.
Goddard, M.
Smith, C.
Menon, D.
Allinson, K. S. J.
[J]. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2021, 47 (01) : 17 - 25
[24] Neuropathogenesis of SARS-CoV-2 infection
Khan, Shumayila
Gomes, James
[J]. ELIFE, 2020, 9 : 1 - 9
[25] Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis
Koertvelyessy, Peter
Goihl, Alexander
Guttek, Karina
Schraven, Burkhart
Pruess, Harald
Reinhold, Dirk
[J]. CYTOKINE, 2020, 135
[26] A novel coronavirus associated with severe acute respiratory syndrome
Ksiazek, TG
Erdman, D
Goldsmith, CS
Zaki, SR
Peret, T
Emery, S
Tong, SX
Urbani, C
Comer, JA
Lim, W
Rollin, PE
Dowell, SF
Ling, AE
Humphrey, CD
Shieh, WJ
Guarner, J
Paddock, CD
Rota, P
Fields, B
DeRisi, J
Yang, JY
Cox, N
Hughes, JM
LeDuc, JW
Bellini, WJ
Anderson, LJ
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (20) : 1953 - 1966
[27] Laue M, 2010, CELL BIOL, V96, P20, DOI [10.1016/S0091-679X(10)96001-9, DOI 10.1016/S0091-679X(10)96001-9]
[28] Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4
Li, Kun
Wohlford-Lenane, Christine
Perlman, Stanley
Zhao, Jincun
Jewell, Alexander K.
Reznikov, Leah R.
Gibson-Corley, Katherine N.
Meyerholz, David K.
McCray, Paul B., Jr.
[J]. JOURNAL OF INFECTIOUS DISEASES, 2016, 213 (05) : 712 - 722
[29] Neuropathology of patients with COVID-19 in Germany: a post-mortem case series
Matschke, Jakob
Luetgehetmann, Marc
Hagel, Christian
Sperhake, Jan P.
Schroeder, Ann Sophie
Edler, Carolin
Mushumba, Herbert
Fitzek, Antonia
Allweiss, Lena
Dandri, Maura
Dottermusch, Matthias
Heinemann, Axel
Pfefferle, Susanne
Schwabenland, Marius
Magruder, Daniel Sumner
Bonn, Stefan
Prinz, Marco
Gerloff, Christian
Pueschel, Klaus
Krasemann, Susanne
Aepfelbacher, Martin
Glatzel, Markus
[J]. LANCET NEUROLOGY, 2020, 19 (11) : 919 - 929
[30] Miao X, 2020, Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study, DOI 10.1101/2020.02.22.20026500

← 1 2 3 4 5 →