Neuroinvasion of SARS-CoV-2 in human and mouse brain
Open accessPreprint — published as 10.1084/jem.20202135 · Paper page
Abstract
Summary: 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.
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Autopsy has revealed that SARS-CoV-2 is detected in subcortical white matter but without infiltration of lymphocytes or leukocytes, although not all post-mortem studies have detected SARS-CoV-2 in the brain.
“For example, autopsy has revealed that SARS-CoV-2 is detected in subcortical white matter but without infiltration of lymphocytes or leukocytes [78], although not all post-mortem studies have detected SARS-CoV-2 in the brain.”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [78]
There has been no evidence for a role of innate immune cells in SARS-CoV-2 gaining access to the retina or the brain, although the virus has been found in both organs.
“Furthermore, there has been no evidence for the role of innate immune cells in SARS-CoV-2 gaining access to the retina (de Figueiredo et al., 2020) or the brain (Song et al., 2021), albeit the virus has been found in both organs.”
From COVID-19 and the human innate immune system (2021) · cites this paper as Song et al., 2021
Once the virus enters the CNS, it affects neurons, microglia, oligodendrocytes, and especially astrocytes, undermining neuron viability.
“Once the virus enters the CNS, it affects neurons, microglia, oligodendrocytes, and especially astrocytes, undermining neurons viability [17, 179, 180].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [180]
Positive staining for SARS-CoV-2 spike protein was found in the brain of three COVID-19 patients, with different expression patterns and staining intensities.
“The same study found positive staining for SARS-CoV-2 spike protein in the brain of three COVID-19 patients, with different expression patterns and staining intensities [26].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [26]
Neuroinvasion potential of SARS-CoV-2 was demonstrated in mice expressing human ACE2 and correlated with increased mortality independent from respiratory infection.
“Neuroinvasion potential of SARS-CoV-2 was demonstrated in mice expressing human ACE2 and correlated with increased mortality independent from respiratory infection [26].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [26]
Neuroinvasion capability of SARS-CoV-2 was observed in human brain organoids, especially in neuronal cells such as neural progenitor and radial glial cells, accompanied by increased cell death.
“neuroinvasion capability of SARS-CoV-2 was observed in human brain organoids, especially in neuronal cells, such as neural progenitor and radial glial cells, accompanied by increased cell death [26].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [26]
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- Authors
- Song, E., Zhang, C., Israelow, B., Lu-Culligan, A., Prado, A. V., Skriabine, S., Lu, P., Weizman, O.-E., Liu, F., Dai, Y., Szigeti-Buck, K., Yasumoto, Y., Wang, G., Castaldi, C., Heltke, J., Ng, E., Wheeler, J., Alfajaro, M. M., Levavasseur, E., Fontes, B., Ravindra, N. G., Van Dijk, D., Mane, S., Gunel, M., Ring, A., Jaffar Kazmi, S. A., Zhang, K., Wilen, C. B., Horvath, T. L., Plu, I., Haik, S., Thomas, J.-L., Louvi, A., Farhadian, S. F., Huttner, A., Seilhean, D., Renier, N., Bilguvar, K., & Iwasaki, A.
- Affiliations
- Yale University (US)
- Centre National de la Recherche Scientifique (FR)
- Geisinger Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Iwasaki, Akiko
- ORCID
- Song, Eric
- Zhang, Ce
- Israelow, Benjamin
- Lu-Culligan, Alice
- Prado, Alba Vieites
- Skriabine, Sophie
- Lu, Peiwen
- Weizman, Orr-El
- Liu, Feimei
- Dai, Yile
- Yasumoto, Yuki
- Wang, Guilin
- Castaldi, Christopher
- Heltke, Jaime
- Ng, Evelyn
- Wheeler, John
- Alfajaro, Mia Madel
- Levavasseur, Etienne
- Fontes, Benjamin
- Ravindra, Neal G.
- Mane, Shrikant
- Ring, Aaron
- Zhang, Kai
- Wilen, Craig B
- Plu, Isabelle
- Louvi, Angeliki
- Farhadian, Shelli F.
- Huttner, Anita
- Seilhean, Danielle
- Renier, Nicolas
- Bilguvar, Kaya
- Iwasaki, Akiko
- Venue
- The Journal of Experimental Medicine
- Publisher
- openRxiv
- Published
- 2020-06-26
- Volume
- 218
- Issue
- 3
- Pages
- e20202135
- ISSN
- 0022-1007 (ISSN-L)
- PMC
- PMC7491522
- OpenAlex
- W3118627743
- Cited by
- 1,064
- References
- 48
- Citations by year
- 2026: 39 · 2025: 80 · 2024: 143 · 2023: 204 · 2022: 278 · 2021: 287 · 2020: 31 · 2015: 1 · 2013: 1
- FWCI
- 87.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- Yale University (T32GM007205)
- G. Harold and Leila Y. Mathers Foundation
- Ludwig Family Foundation
- Agence Nationale de la Recherche (ANR-17-CE14-0005)
- National Institutes of Health (UL1TR001863)
- National Institute of Mental Health (K23MH118999)
- National Cancer Institute (F30CA239444)
- National Institute of General Medical Sciences (T32GM007205)
- National Institute of Allergy and Infectious Diseases (R01AI157488, T32AI055403, T32AI007517)
- National Institute of Neurological Disorders and Stroke (R01NS111242)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, neuroinvasion, central nervous system infection, brain organoids, neuronal infection, ACE2, type I interferon response, cerebrospinal fluid, transgenic mouse model, autopsy findings, cortical neurons, immune cell infiltration
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