SARS-CoV-2 infects human neural progenitor cells and brain organoids

Zhang, Baozhong; Chu, Hin; Han, Shuo; Shuai, Huiping; Deng, Jian Min; Hu, Ye-Fan; Gong, Hua‐Rui; Lee, Andrew Chak-Yiu; Zou, Zijiao; Yau, Thomas; Wu, Wutian; Hung, Ivan; Chan, Jasper Fuk‐Woo; Yuen, Kwok‐Yung; Huang, Jiandong

doi:10.1038/s41422-020-0390-x

Cited by 294 publications

(373 citation statements)

References 13 publications

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“…2c). Thus, unlike recent reports where SARS-CoV-2 was added directly to neuroglial organoids lacking brain-barrier cells 21–25 , we do not observe significant virus invasion in cortex parenchymal cells. On the other hand, SARS-CoV-2 infection of the CSF-barrier forming choroid plexus and meninges corroborates recent in vitro, in silico , CSF, and postmortem case studies suggesting CNS barrier cells can support productive infection at relatively low titers 5,23,24,42,43 .…”

Section: Sars-cov-2 Accumulation In Barrier Cells Stimulates Inflammacontrasting

confidence: 99%

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Yang

Kern

et al. 2020

Preprint

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Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

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Section: Sars-cov-2 Accumulation In Barrier Cells Stimulates Inflammacontrasting

confidence: 99%

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Yang

Kern

et al. 2020

Preprint

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“…Sequencing analysis of human-derived tissues has identified a variety of primary cells that express the ACE2 receptors and other co-factors necessary for the infection 12,22 . Ex vivo infectivity assays have confirmed the infectibility of some of these cells by SARS-CoV-2 23–25 . The surface expression level of ACE2 on these cells varies greatly 26 .…”

Section: Resultsmentioning

confidence: 83%

The SARS-CoV-2 Spike mutation D614G increases entry fitness across a range of ACE2 levels, directly outcompetes the wild type, and is preferentially incorporated into trimers

Michaud

Boland

Rabi

2020

Preprint

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Early in the current pandemic, the D614G mutation arose in the Spike protein of SARS-CoV-2 and quickly became the dominant variant globally. Mounting evidence suggests D614G enhances viral entry. Here we use a direct competition assay with single-cycle viruses to show that D614G outcompetes the wildtype. We developed a cell line with inducible ACE2 expression to confirm that D614G more efficiently enters cells with ACE2 levels spanning the different primary cells targeted by SARS-CoV-2. Using a new assay for crosslinking and directly extracting Spike trimers from the pseudovirus surface, we found an increase in trimerization efficiency and viral incorporation of D614G protomers. Our findings suggest that D614G increases infection of cells expressing a wide range of ACE2, and informs the mechanism underlying enhanced entry. The tools developed here can be broadly applied to study other Spike variants and SARS-CoV-2 entry, to inform functional studies of viral evolution and vaccine development.

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“…Here, we clarified the expression of ACE2 in both brain organoids and 2D cortical neurons. Previous studies showed that SARS-CoV-2 can enter into brainspheres that are 3D spheroids of differentiated neurons [23,24]. In addition to a culture of one neuronal cell type, we here employed an organoid model which contains mixed cell types with structural boundaries.…”

Section: Discussionmentioning

confidence: 99%

Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus

Nam

Yun

et al. 2020

Viruses

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Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.

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SARS-CoV-2 infects human neural progenitor cells and brain organoids

Cited by 294 publications

References 13 publications

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

The SARS-CoV-2 Spike mutation D614G increases entry fitness across a range of ACE2 levels, directly outcompetes the wild type, and is preferentially incorporated into trimers

Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus

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