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Authors: Ramani, Müller, and Ostermann et al.

Link to paper: https://doi.org/10.1101/2020.05.20.106575

Journal/ Pre-Print: Biorxiv

Tags: Neurobiology, cell biology

Research Highlights 

1. Infection of human brain organoid by SARS-CoV2

2. Potential pathological phenotypes triggered by SARS-CoV2

Summary

A small portion of COVID19 patients exhibited neurological symptoms indicating that SARS-CoV2 is neurotopic. This study offers the first indication that SARS-CoV2 may directly interact with neurons using 3D cerebral organoids. The authors report that this virus preferentially infected cortical neurons and not neural stem cells, in organoids. While, SARS-CoV2 readily infects the cells it does not replicate in the brain organoid. Additionally, infection by SARS-CoV2 appeared to activate hyperphosphorylation of Tau and subsequent neuronal cell death. Although the study demonstrates cerebral organoids as a suitable model system to study neurotropic phase of SARS-CoV2, it does not clearly discern the cause and effect of this observation.

Impact for SARS-CoV2/COVID19 research efforts

3D brain or cerebral organoid is a suitable model system to study SARS-CoV2-CNS intearctions

Experimental validation of potential neuron damage by SARS-CoV2

In spite of low ACE-2 expression in the brain organoids, SARS-CoV2 productively infects and causes neuronal cell death

Study Type

In vitro study

Strengths and limitations of the paper

Novelty: Brain organoid model of CoVID19

Standing in the field: This is the first study that demonstrates that SARS-COV2 infects cortical neurons in the brain.

Appropriate statistics: Figure 2E appeared to have a very different variance so Tukey multiple testing might not be a good choice. The alternative shall be Games-Howell test. The authors also needed to test the normality and equality of variance of data before decided to use what type of ANOVA.

Viral model used: Düsseldorf isolate of SARS-CoV2 and 3D brain organoid

Translatability: More experimental validation using primary cell systems and differentiated organodis needed to determine its translational potential.

Main limitations:

- The paper did not indicate the mechanism of viral entry into mature neuron

- Figure 2E suggested the percentage of SARS-CoV2 was higher in neuron cultured for 60 days. Authors suggested that it was due to the presence of increased differentiated cells. However, they did not present clear data to support this argument. A higher percentage could also be triggered due to fewer total cells which could be caused by a higher cell death as suggested in Figure 4B.

- Weak data for the claim – figure 2E doesn’t support data.

- Tau hyperphosphorylation data is weak

- The number of dead cells is far greater than the number of infected cells.