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Authors: Song et al. 

Journal/ Pre-Print: BioRxiv 

Tags: Cell Biology, Inflammation, Molecular Biology, Virology  

Research Highlights 

  1. SARS-CoV-2 can infect human brain organoids resulting in unique metabolic changes and the death of infected and neighbouring neurons. 

  1. Neural infection can be prevented by using either anti-ACE2 antibodies or anti-spike antibodies from the cerebrospinal fluid (CSF) of COVID-19 patients. 

  1. SARS-CoV-2 infected mice overexpressing human ACE2 showed increase viral titers in the brain and death associated to neuroinvasion. 

  1. SARS-CoV-2 infected mice expressing hACE2 in the brain die more than mice expressing hACE2 in the lungs 

Summary 

This study explorethe potential of SARS-CoV-2 to infect the brain and replicate in neural tissues of both mice and human origin. Using induced pluripotent stem cell (hiPSC) lines derived from healthy individuals, the authors generated human brain organoids to model SARS-CoV-2 infection of neuronal cells in three-dimension. Results showed extensive cell death and metabolic changes in both infected and neighbouring neurons with no evidence of IFN or ISG response. Organoids incubated with either anti-ACE2 antibodies or anti-spike antibodies from the CSF of COVID-19 patients saw a significant decrease in SARS-CoV-2 infection. Likewise, transgenic mice overexpressing human ACE2 were used to demonstrate viral replication in the brain and the lethal consequences of SARS-CoV-2 CNS infection. 

Impact for SARS-CoV2/COVID19 Research Efforts  

  • Clinical symptoms and pathogenesis of SARS-Cov2/COVID19 

Study Type 

  • In vivo study (e.g. mouse, NHP) 

  • In vitro study 

Strengths and Limitations of the Paper 

Novelty: They provide in vivo evidence for the neuroinvasive potential of SARS-CoV-2. 

Standing in the field: CNS associated symptoms (e.g. headaches, impaired consciousnesshave been reported in 30-60% of COVID-19 cases. Similarly, some autopsies on patients who passed away from COVID have shown viral RNA transcripts and proteins to be present in brain tissue. A previous report by Ramani et al. (2020) had reported that SARS-CoV-2 targets cortical neurons of human brain organoids:  

Appropriate statistics: Yes 

Viral model used: SARS-CoV-2 isolate USA-WA1/2020 

Translatability: Not directly translatable but provides valuable insight into the tissue tropism and pathogenesis of the virusAs shown in this paper, direct viral invasion of the CNS might explain some of the neurologic symptoms seen in the clinic. Furthermore, the murine model and hiPSC model described could be extended for infection studies and compound testing. 

Main limitations: 

  • No technical replicates for experiments using transgenic mice (Fig. 4A, 4B). 

  • No biological replicates for experiments with organoids (experiment run once with n = 4 organoids per condition).