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

Gopalakrishnan, J.; Ramani, A.; Mueller, L.; Niklas Ostermann, P.; Gabriel, E.; Islam Pranty, A.; Mueller-Shiffmann, A.; Mariappan, A.; Goureau, O.; Gruell, H.; Walker, A.; Andree, M.; Hauka, S.; Wohlgemuth, K.; Omran, H.; Klein, F.; Wieczorek, D.; Adams, O.; Timm, J.; Korth, C.; Schaal, H.; Houwaart, T.; Dilthey, A.

doi:10.1101/2020.05.20.106575

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bioRxiv · 10.1101/2020.05.20.106575

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

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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 Dusseldorf 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 summaryCOVID-19 modeling in human brain organoids

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Gopalakrishnan, J., Ramani, A., Mueller, L., Niklas Ostermann, P., Gabriel, E., Islam Pranty, A., Mueller-Shiffmann, A., Mariappan, A., Goureau, O., Gruell, H., Walker, A., Andree, M., Hauka, S., Wohlgemuth, K., Omran, H., Klein, F., Wieczorek, D., Adams, O., Timm, J., Korth, C., Schaal, H., Houwaart, T., Dilthey, A.. 2020-05-20. SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects. https://doi.org/10.1101/2020.05.20.106575

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