Neuroinvasion of SARS-CoV-2 in human and mouse brain

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Neuroinvasion of SARS-CoV-2 in human and mouse brain

View ORCID ProfileEric Song, Ce Zhang, View ORCID ProfileBenjamin Israelow, Alice Lu-Culligan, Alba Vieites Prado, Sophie Skriabine, 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, Etienne Levavasseur, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Syed A. Jaffar Kazmi, Kai Zhang, Craig B Wilen, Tamas L. Horvath, Isabelle Plu, Stephane Haik, Jean-Leon Thomas, Angeliki Louvi, View ORCID ProfileShelli F. Farhadian, Anita Huttner, Danielle Seilhean, Nicolas Renier, View ORCID ProfileKaya Bilguvar, View ORCID ProfileAkiko Iwasaki

doi: https://doi.org/10.1101/2020.06.25.169946

This article is a preprint and has not been certified by peer review [what does this mean?].

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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). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, 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. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

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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.