Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients

Mona Khan; Marnick Clijsters; Sumin Choi; Wout Backaert; Michiel Claerhout; Floor Couvreur; Laure Van Breda; Florence Bourgeois; Kato Speleman; Sam Klein; Johan Van Laethem; Gill Verstappen; Ayse Sumeyra Dereli; Seung-Jun Yoo; Hai Zhou; Thuc Nguyen Dan Do; Dirk Jochmans; Lies Laenen; Yves Debaveye; Paul De Munter; Jan Gunst; Mark Jorissen; Katrien Lagrou; Philippe Meersseman; Johan Neyts; Dietmar Rudolf Thal; Vedat Topsakal; Christophe Vandenbriele; Joost Wauters; Peter Mombaerts; Laura Van Gerven

doi:10.1016/j.neuron.2022.11.007

Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients

Mona Khan, Marnick Clijsters, Sumin Choi, Wout Backaert, Michiel Claerhout, Floor Couvreur, Laure Van Breda, Florence Bourgeois, Kato Speleman, Sam Klein, Johan Van Laethem, Gill Verstappen, Ayse Sumeyra Dereli, Seung-Jun Yoo, Hai Zhou, Thuc Nguyen Dan Do, Dirk Jochmans, Lies Laenen, Yves Debaveye, Paul De MunterJan Gunst, Mark Jorissen, Katrien Lagrou, Philippe Meersseman, Johan Neyts, Dietmar Rudolf Thal, Vedat Topsakal, Christophe Vandenbriele, Joost Wauters, Peter Mombaerts, Laura Van Gerven

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Abstract

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa.

Original language	English
Pages (from-to)	3919-3935.e6
Number of pages <span style="color:red"p> <font size="1.5"> ✽ </span> </font>	17
Journal	Neuron
Volume	110
Issue number	23
Early online date	10 Nov 2022
DOIs	https://doi.org/10.1016/j.neuron.2022.11.007
Publication status	Published - 7 Dec 2022

Bibliographical note

Funding Information:
We thank the nurses, doctors, and paramedical staff for their support and cooperation; Piet Maes and Björn Rötter for help with variant determination; Arthur Goby, Peter Leemans, Ling Li, Florian Lindenblatt, and Edisa Turkovic for technical support; Patrick Meeze for drawings; and Thomas Boehm and Simon Feys for comments on a draft. T.N.D.D. received a fellowship from EU Horizon 2020 grant OrganoVIR “Organoids for Virus Research - An innovative training - ITN programme.” C.V. and L.V.G. were supported by FWO Senior Clinical Investigator Fellowships 1803923N and 18B2222N , respectively. J.N. was supported by Covid-19-Fund KU Leuven /UZ Leuven and the COVID-19 call of FWO ( G0G4820N ). D.R.T. received support from FWO ( G0F8516N , G065721N ), Stichting Alzheimer Onderzoek (SAO-FRA Belgium, 2020/017 ), and KU Leuven Internal Funding ( C14/17/107 ; C14/22/132 ). P. Mombaerts received financial support from the Max Planck Society .

Publisher Copyright:
© 2022 The Author(s)

Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.

Keywords

COVID-19
Coronavirus
Delta
Omicron
RNAscope
SARS-CoV-2;
Virchow-Robin space
blood-brain barrier
brain parenchyma
frontal lobe
glia limitans perivascularis
leptomeninges
neuroinvasion
neurotropism
olfactory
olfactory bulb
olfactory sensory neuron
perineurial olfactory
nerve fibroblast

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Khan, M., Clijsters, M., Choi, S., Backaert, W., Claerhout, M., Couvreur, F., Van Breda, L., Bourgeois, F., Speleman, K., Klein, S., Van Laethem, J., Verstappen, G., Dereli, A. S., Yoo, S-J., Zhou, H., Dan Do, T. N., Jochmans, D., Laenen, L., Debaveye, Y., ... Van Gerven, L. (2022). Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients. Neuron, 110(23), 3919-3935.e6. https://doi.org/10.1016/j.neuron.2022.11.007

Khan, Mona ; Clijsters, Marnick ; Choi, Sumin ; Backaert, Wout ; Claerhout, Michiel ; Couvreur, Floor ; Van Breda, Laure ; Bourgeois, Florence ; Speleman, Kato ; Klein, Sam ; Van Laethem, Johan ; Verstappen, Gill ; Dereli, Ayse Sumeyra ; Yoo, Seung-Jun ; Zhou, Hai ; Dan Do, Thuc Nguyen ; Jochmans, Dirk ; Laenen, Lies ; Debaveye, Yves ; De Munter, Paul ; Gunst, Jan ; Jorissen, Mark ; Lagrou, Katrien ; Meersseman, Philippe ; Neyts, Johan ; Thal, Dietmar Rudolf ; Topsakal, Vedat ; Vandenbriele, Christophe ; Wauters, Joost ; Mombaerts, Peter ; Van Gerven, Laura. / Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients. In: Neuron. 2022 ; Vol. 110, No. 23. pp. 3919-3935.e6.

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abstract = "Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa.",

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Khan, M, Clijsters, M, Choi, S, Backaert, W, Claerhout, M, Couvreur, F, Van Breda, L, Bourgeois, F, Speleman, K, Klein, S, Van Laethem, J , Verstappen, G, Dereli, AS, Yoo, S-J, Zhou, H, Dan Do, TN, Jochmans, D, Laenen, L, Debaveye, Y, De Munter, P, Gunst, J, Jorissen, M, Lagrou, K, Meersseman, P, Neyts, J, Thal, DR, Topsakal, V, Vandenbriele, C, Wauters, J, Mombaerts, P & Van Gerven, L 2022, 'Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients', Neuron, vol. 110, no. 23, pp. 3919-3935.e6. https://doi.org/10.1016/j.neuron.2022.11.007

Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients. / Khan, Mona; Clijsters, Marnick; Choi, Sumin; Backaert, Wout; Claerhout, Michiel; Couvreur, Floor; Van Breda, Laure; Bourgeois, Florence; Speleman, Kato; Klein, Sam; Van Laethem, Johan ; Verstappen, Gill; Dereli, Ayse Sumeyra; Yoo, Seung-Jun; Zhou, Hai; Dan Do, Thuc Nguyen; Jochmans, Dirk; Laenen, Lies; Debaveye, Yves; De Munter, Paul; Gunst, Jan; Jorissen, Mark; Lagrou, Katrien; Meersseman, Philippe; Neyts, Johan; Thal, Dietmar Rudolf; Topsakal, Vedat; Vandenbriele, Christophe; Wauters, Joost; Mombaerts, Peter; Van Gerven, Laura.

In: Neuron, Vol. 110, No. 23, 07.12.2022, p. 3919-3935.e6.

Research output: Contribution to journal › Article › peer-review

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AU - Gunst, Jan

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AU - Neyts, Johan

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Y1 - 2022/12/7

N2 - Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa.

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Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients

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Keywords

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