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Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model

View ORCID ProfileEric Song, Ce Zhang, View ORCID ProfileBenjamin Israelow, View ORCID ProfilePeiwen Lu, View ORCID ProfileOrr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Craig B Wilen, Tamas L. Horvath, Angeliki Louvi, View ORCID ProfileShelli F. Farhadian, View ORCID ProfileKaya Bilguvar, View ORCID ProfileAkiko Iwasaki
doi: https://doi.org/10.1101/2020.06.25.169946
Eric Song
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Ce Zhang
2Department of Genetics, Yale School of Medicine, New Haven, CT, USA
3Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
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Benjamin Israelow
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
4Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
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Peiwen Lu
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Orr-El Weizman
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Feimei Liu
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
5Department of Biomedical Engineering, Yale University, New Haven, CT, USA
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Yile Dai
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Klara Szigeti-Buck
3Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
6Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
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Yuki Yasumoto
3Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
6Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
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Guilin Wang
7Yale Center for Genome Analysis, West Haven, CT, USA
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Christopher Castaldi
7Yale Center for Genome Analysis, West Haven, CT, USA
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Jaime Heltke
7Yale Center for Genome Analysis, West Haven, CT, USA
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Evelyn Ng
7Yale Center for Genome Analysis, West Haven, CT, USA
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John Wheeler
7Yale Center for Genome Analysis, West Haven, CT, USA
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Mia Madel Alfajaro
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
8Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
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Benjamin Fontes
9Yale Environmental Health and Safety, Yale University, New Haven, CT, USA
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Neal G. Ravindra
10Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
11Department of Computer Science, Yale University, New Haven, CT, USA
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David Van Dijk
10Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
11Department of Computer Science, Yale University, New Haven, CT, USA
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Shrikant Mane
2Department of Genetics, Yale School of Medicine, New Haven, CT, USA
7Yale Center for Genome Analysis, West Haven, CT, USA
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Murat Gunel
2Department of Genetics, Yale School of Medicine, New Haven, CT, USA
3Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
12Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
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Aaron Ring
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Craig B Wilen
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
8Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
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Tamas L. Horvath
6Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
13Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA
14Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT, USA
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Angeliki Louvi
3Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
12Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
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Shelli F. Farhadian
4Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
15Department of Neurology, Yale School of Medicine, New Haven, CT, USA
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Kaya Bilguvar
2Department of Genetics, Yale School of Medicine, New Haven, CT, USA
7Yale Center for Genome Analysis, West Haven, CT, USA
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Akiko Iwasaki
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
14Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT, USA
16Howard Hughes Medical Institute, Chevy Chase, MD, USA
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Abstract

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Reports indicate that 30-60% of patients with COVID-19 suffer from CNS symptoms. Yet, there is no consensus whether the virus can infect the brain, or what the consequences of infection are. Following SARS-CoV-2 infection of human brain organoids, clear evidence of infection was observed, with accompanying metabolic changes in the infected and neighboring neurons. Further, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Finally, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV2.

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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 26, 2020.
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Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model
Eric Song, Ce Zhang, Benjamin Israelow, Peiwen Lu, Orr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Craig B Wilen, Tamas L. Horvath, Angeliki Louvi, Shelli F. Farhadian, Kaya Bilguvar, Akiko Iwasaki
bioRxiv 2020.06.25.169946; doi: https://doi.org/10.1101/2020.06.25.169946
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Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model
Eric Song, Ce Zhang, Benjamin Israelow, Peiwen Lu, Orr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Craig B Wilen, Tamas L. Horvath, Angeliki Louvi, Shelli F. Farhadian, Kaya Bilguvar, Akiko Iwasaki
bioRxiv 2020.06.25.169946; doi: https://doi.org/10.1101/2020.06.25.169946

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