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SARS-CoV-2 infects brain choroid plexus and disrupts the blood-CSF-barrier

Laura Pellegrini, Anna Albecka, Donna L. Mallery, Max J. Kellner, David Paul, Andrew P. Carter, Leo C. James, View ORCID ProfileMadeline A. Lancaster
doi: https://doi.org/10.1101/2020.08.20.259937
Laura Pellegrini
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Anna Albecka
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Donna L. Mallery
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Max J. Kellner
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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David Paul
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Andrew P. Carter
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Leo C. James
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Madeline A. Lancaster
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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  • ORCID record for Madeline A. Lancaster
  • For correspondence: madeline.lancaster@mrc-lmb.cam.ac.uk
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Abstract

Coronavirus disease-19 (COVID-19), caused by the SARS-CoV-2 virus, leads primarily to respiratory symptoms that can be fatal, particularly in at risk individuals. However, neurological symptoms have also been observed in patients, including headache, seizures, stroke, and fatigue. The cause of these complications is not yet known, and whether they are due to a direct infection of neural cells, such as neurons and astrocytes, or through indirect effects on supportive brain cells, is unknown. Here, we use brain organoids to examine SARS-CoV-2 neurotropism. We examine expression of the key viral receptor ACE2 in single-cell RNA sequencing (scRNA-seq) revealing that only a subset of choroid plexus cells but not neurons or neural progenitors express this entry factor. We then challenge organoids with both SARS-CoV-2 spike protein pseudovirus and live virus to demonstrate high viral tropism for choroid plexus epithelial cells but not stromal cells, and little to no infection of neurons or glia. We find that infected cells of the choroid plexus are an apolipoprotein and ACE2 expressing subset of epithelial barrier cells. Finally, we show that infection with live SARS-CoV-2 leads to barrier breakdown of the choroid plexus. These findings suggest that neurological complications may result from effects on the choroid plexus, an important barrier that normally prevents entry of immune cells and cytokines into the cerebrospinal fluid (CSF) and brain.

Competing Interest Statement

The authors have filed a patent based on ChP organoids.

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-ND 4.0 International license.
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Posted August 21, 2020.
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SARS-CoV-2 infects brain choroid plexus and disrupts the blood-CSF-barrier
Laura Pellegrini, Anna Albecka, Donna L. Mallery, Max J. Kellner, David Paul, Andrew P. Carter, Leo C. James, Madeline A. Lancaster
bioRxiv 2020.08.20.259937; doi: https://doi.org/10.1101/2020.08.20.259937
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SARS-CoV-2 infects brain choroid plexus and disrupts the blood-CSF-barrier
Laura Pellegrini, Anna Albecka, Donna L. Mallery, Max J. Kellner, David Paul, Andrew P. Carter, Leo C. James, Madeline A. Lancaster
bioRxiv 2020.08.20.259937; doi: https://doi.org/10.1101/2020.08.20.259937

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