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

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

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 Düsseldorf 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 summary COVID-19 modeling in human brain organoids