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

Gopalakrishnan, Jay; Ramani, Anand; Mueller, Lisa; Ostermann, Philipp Niklas; Gabriel, Elke; Pranty, Abida Islam; Mueller-Shiffmann, Andreas; Mariappan, Aruljothi; Goureau, Olivier; Gruell, Henning; Walker, Andreas; Andrée, Marcel; Hauka, Sandra; Wohlgemuth, Kai; Omran, Heymut; Klein, Florian; Wieczorek, Dagmar; Adams, Ortwin; Timm, Joerg; Korth, Carsten; Schaal, Heiner; Houwaart, Torsten; Dilthey, Alexander

doi:10.1101/2020.05.20.106575

Cited by 30 publications

(35 citation statements)

References 39 publications

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“…Recent reports have similarly explored neurotropism of SARS-CoV-2 using brain organoids and neurospheres, but with contradictory findings to those we observed here (Ramani et al, 2020;Song et al, 2020). One possible explanation is the use of pseudovirus versus live SARS-CoV-2, with other reports making use of live viral isolates.…”

Section: Sars-cov-2 Spike Pseudovirus Only Infects Chp Cells Of Braincontrasting

confidence: 87%

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

Pellegrini

Albecka

Mallery

et al. 2020

Preprint

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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.

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Section: Sars-cov-2 Spike Pseudovirus Only Infects Chp Cells Of Braincontrasting

confidence: 87%

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

Pellegrini

Albecka

Mallery

et al. 2020

Preprint

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“…Next, we generated hiPSC-derived brain organoids (Amin and Pasca, 2018;Pellegrini et al, 2020;Qian et al, 2016;Velasco et al, 2019) to model the SARS-CoV-2 infection of neuronal cells in 3D. Similar to a recent report (Ramani et al, 2020), we observed infection of neuronal cells in nine-week-old organoids as early as 24 hpi, with significantly increased number of SARS-CoV-2 positive cells at 96 hpi ( Figure 1A-C, Figure S2C). Although the majority of the SARS-CoV-2 infected cells were localized within MAP2 positive cellular fields of mature neurons ( Figure 1B.2, Figure S2C), we also observed infection of SOX2-positive neural stem cells with bipolar morphology and cells localized around the neural tube-like structures ( Figure 1B.1).…”

Section: Modeling Sars-cov-2 Neuroinvasion and Cellular Death Using Hsupporting

confidence: 83%

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

Song

Zhang

Israelow

et al. 2020

Preprint

275

380

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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.

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“…The information currently available is from research on SARS-CoV, which has 78% nucleotide homology with SARS-CoV-2 ( 18 ). Although CNS tropism has been described ( 20 ), no specific models of neural cell lines have been developed for the study of SARS-CoV-2; however, neural progenitor cells (NPCs), neurons and microglia derived from human induced pluripotent stem cells (hIPSCs) have already been used in in vitro studies of SARS-CoV-2 viral infection, demonstrating the virus potential to infect CNS cells ( 116 – 118 ). Previous studies with other neurotropic human coronaviruses showed possible neural cell lines susceptible to infection by SARS-CoV-2 that may be useful in studying the possible mechanisms by which the virus infects the CNS.…”

Section: Cns Cell Linesmentioning

confidence: 99%

Section: Brain Organoids As a Model Of Cns Infection By Sars-cov-2mentioning

confidence: 99%

“…Ramani et al ( 116 ) observed that in these brain organoids, the virus mainly infects mature cortical neurons and presents a perinuclear distribution within these cells. Furthermore, neurodegenerative effects have been observed in cells infected by SARS-CoV-2, including cell death and hyperphosphorylation, as well as mislocation of Tau protein; these alterations are observed in such conditions as tauopathies or Alzheimer disease ( 116 ). However, no productive replication of the virus was observed in these cells, at least in the first 4 days after infection ( 116 ), which would support the hypothesis that the CNS may act as a long-term reservoir of the virus ( 10 ).…”

Section: Brain Organoids As a Model Of Cns Infection By Sars-cov-2mentioning

confidence: 99%

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Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2

et al. 2020

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Introduction The response to the SARS-CoV-2 coronavirus epidemic requires increased research efforts to expand our knowledge of the disease. Questions related to infection rates and mechanisms, the possibility of reinfection, and potential therapeutic approaches require us not only to use the experimental models previously employed for the SARS-CoV and MERS-CoV coronaviruses but also to generate new models to respond to urgent questions. Development We reviewed the different experimental models used in the study of central nervous system (CNS) involvement in COVID-19 both in different cell lines that have enabled identification of the virus’ action mechanisms and in animal models (mice, rats, hamsters, ferrets, and primates) inoculated with the virus. Specifically, we reviewed models used to assess the presence and effects of SARS-CoV-2 on the CNS, including neural cell lines, animal models such as mouse hepatitis virus CoV (especially the 59 strain), and the use of brain organoids. Conclusion Given the clear need to increase our understanding of SARS-CoV-2, as well as its potential effects on the CNS, we must endeavor to obtain new information with cellular or animal models, with an appropriate resemblance between models and human patients.

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

Cited by 30 publications

References 39 publications

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

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

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

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2

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