SARS ‐CoV‐2 targets neurons of 3D human brain organoids

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 Düsseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within 2 days of exposure. We identified that SARS-CoV-2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS-CoV-2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS-CoV-2 and emphasize that brain organoids could model CNS pathologies of COVID-19.

3D reconstruction of SARS-CoV-2 infection in ferrets emphasizes focal infection pattern in the upper respiratory tract

“…For instance, viral antigen has been detected in the intestine of ferrets [29], hamsters [32,33], and rhesus macaques [42]. While viral RNA has been detected in human clinical brain samples [64], infection of cells of the central nervous system could thus far only be demonstrated experimentally in 3D human brain organoids [65]. Except for genetically modified mice expressing human angiotensin-converting enzyme 2 (ACE2) [39], the presence of SARS-CoV-2 antigen in animal or human brain samples has yet to be shown.…”

Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

“…Relatively mature neurons in day 60 COs exhibited substantial SARS-CoV-2 infection in cortical neurons within two days of exposure compared to Day 15 COs [67]. Similar viral load between two-and four-day post infection in COs indicated that the virus did not actively replicate in the COs [67]. Interestingly, the infected COs also showed an increase in early neurodegeneration-like phenotype as pTau (T231) was missorted from the axon to the soma and was colocalized with SARS-CoV-2 [67].…”

“…Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes severe upper respiratory tract infection and has also been shown to cause neurological symptoms [66]. Two recent studies have explored the neurological effects of this virus in COs [67,68] ( [68] published as preprint in bioRxiv). Day 15 and Day 60 COs were exposed to SARS-CoV-2 [67].…”

“…Two recent studies have explored the neurological effects of this virus in COs [67,68] ( [68] published as preprint in bioRxiv). Day 15 and Day 60 COs were exposed to SARS-CoV-2 [67]. Relatively mature neurons in day 60 COs exhibited substantial SARS-CoV-2 infection in cortical neurons within two days of exposure compared to Day 15 COs [67].…”

“…Day 15 and Day 60 COs were exposed to SARS-CoV-2 [67]. Relatively mature neurons in day 60 COs exhibited substantial SARS-CoV-2 infection in cortical neurons within two days of exposure compared to Day 15 COs [67]. Similar viral load between two-and four-day post infection in COs indicated that the virus did not actively replicate in the COs [67].…”