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SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects

Anand Ramani, Lisa Müller, Philipp Niklas Ostermann, Elke Gabriel, Pranty Abida-Islam, Andreas Müller-Schiffmann, Aruljothi Mariappan, Olivier Goureau, Henning Gruell, Andreas Walker, Marcel Andrée, Sandra Hauka, Torsten Houwaart, Alexander Dilthey, Kai Wohlgemuth, Heymut Omran, Florian Klein, Dagmar Wieczorek, Ortwin Adams, Jörg Timm, Carsten Korth, Heiner Schaal, Jay Gopalakrishnan
doi: https://doi.org/10.1101/2020.05.20.106575
Anand Ramani
1Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Lisa Müller
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Philipp Niklas Ostermann
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Elke Gabriel
1Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Pranty Abida-Islam
1Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Andreas Müller-Schiffmann
3Institute of Neuropathology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Aruljothi Mariappan
1Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Olivier Goureau
4Institut de la Vision, Sorbonne Université, INSERM, CNRS, F-75012 Paris, France
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Henning Gruell
5Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Andreas Walker
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Marcel Andrée
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Sandra Hauka
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Torsten Houwaart
6Institute of Medical Microbiology and Hygiene, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Alexander Dilthey
6Institute of Medical Microbiology and Hygiene, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Kai Wohlgemuth
7Department of General Pediatrics, University Children’s Hospital Muenster, 48149 Muenster, Germany
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Heymut Omran
7Department of General Pediatrics, University Children’s Hospital Muenster, 48149 Muenster, Germany
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Florian Klein
5Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
8German Center for Infection Research (DZIF), partner site Bonn-Cologne
9Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
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Dagmar Wieczorek
1Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Ortwin Adams
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Jörg Timm
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Carsten Korth
3Institute of Neuropathology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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Heiner Schaal
2Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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  • For correspondence: schaal@uni-duesseldorf.de jay.gopalakrishnan@hhu.de
Jay Gopalakrishnan
1Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany
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  • For correspondence: schaal@uni-duesseldorf.de jay.gopalakrishnan@hhu.de
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Abstract

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Düsseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within two days of exposure. Using COVID-19 convalescent serum, we identified that SARS-CoV-2 preferably targets soma of cortical neurons but not neural stem cells, the target cell type of ZIKA virus. Imaging cortical neurons of organoids reveal that SARS-CoV-2 exposure is associated with missorted Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Surprisingly, SARS-CoV-2 co-localizes specifically with Tau phosphorylated at Threonine-231 in the soma, indicative of early neurodegeneration-like effects. Our studies, therefore, provide initial insights into the impact of SARS-CoV-2 as a neurotropic virus and emphasize that brain organoids could model CNS pathologies of COVID-19.

One sentence summary COVID-19 modeling in human brain organoids

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 20, 2020.
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SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects
Anand Ramani, Lisa Müller, Philipp Niklas Ostermann, Elke Gabriel, Pranty Abida-Islam, Andreas Müller-Schiffmann, Aruljothi Mariappan, Olivier Goureau, Henning Gruell, Andreas Walker, Marcel Andrée, Sandra Hauka, Torsten Houwaart, Alexander Dilthey, Kai Wohlgemuth, Heymut Omran, Florian Klein, Dagmar Wieczorek, Ortwin Adams, Jörg Timm, Carsten Korth, Heiner Schaal, Jay Gopalakrishnan
bioRxiv 2020.05.20.106575; doi: https://doi.org/10.1101/2020.05.20.106575
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SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects
Anand Ramani, Lisa Müller, Philipp Niklas Ostermann, Elke Gabriel, Pranty Abida-Islam, Andreas Müller-Schiffmann, Aruljothi Mariappan, Olivier Goureau, Henning Gruell, Andreas Walker, Marcel Andrée, Sandra Hauka, Torsten Houwaart, Alexander Dilthey, Kai Wohlgemuth, Heymut Omran, Florian Klein, Dagmar Wieczorek, Ortwin Adams, Jörg Timm, Carsten Korth, Heiner Schaal, Jay Gopalakrishnan
bioRxiv 2020.05.20.106575; doi: https://doi.org/10.1101/2020.05.20.106575

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