Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium

Jacob, Fadi; Pather, Sarshan R.; Huang, Wei‐Kai; Zhang, Feng; Wong, Samuel Zheng Hao; Zhou, Haowen; Cubitt, Beatrice; Fan, Wenqiang; Chen, Catherine Z.; Xu, Miao; Pradhan, Manisha; Zhang, Daniel Y.; Zheng, Wei; Bang, Anne G.; Song, Hongjun; Torre, Juan Carlos de la; Ming, Guo‐li

doi:10.1016/j.stem.2020.09.016

Cited by 332 publications

(467 citation statements)

References 85 publications

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“…To investigate the possibility of viral integration into virus infected cells we analyzed published RNA-Seq data from SARS-CoV-2 -infected cells for evidence of chimeric transcripts, which would be indicative of viral integration into the genome and expression. Examination of these data sets [24][25][26][27][28][29][30] (Fig. S1a-b) revealed a substantial number of host-viral chimeric reads (Fig. 1a-c, S1c).…”

Section: Expression Of Viral-cellular Chimeric Transcripts In Infectementioning

confidence: 99%

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Zhang

Richards

Khalil

et al. 2020

Preprint

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SummaryProlonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious1–14. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

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Section: Expression Of Viral-cellular Chimeric Transcripts In Infectementioning

confidence: 99%

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Zhang

Richards

Khalil

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Recent studies report mixed findings concerning the presence of coronavirus viral RNA and antibodies in the cerebral spinal fluid (CSF) of COVID-19 patients ( 5 , 6 ). However, choroid plexus organoids containing the cell type that produces CSF, can readily be infected by SARS-CoV-2 in vitro ( 7 , 8 ). Together, these studies suggest the capacity for viral transmission into the CNS through the nasal epithelium and/or CSF.…”

Section: Introductionmentioning

confidence: 99%

“…Data from cerebral organoids, which are reflective of developmental stages, suggest that in vitro neurons may be vulnerable to SARS-CoV-2 infection. However the results regarding susceptibility of neurons of different brain regional identities have been mixed across studies and the capacity to infect other neural cell types, including glia, has not been extensively explored ( 7 , 8 , 24 ). Here we utilized primary developing human cortical tissue and cortical organoid models across neurogenic and gliogenic stages to evaluate whether human neural cells can be infected by SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Andrews

Mukhtar

Eze

et al. 2021

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury.

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“…to inflammatory cellular responses and cell death 128 . These findings were corroborated by Pellegrini et al, who used hPSC-derived cortical organoids and choroid plexus organoids to study the tropism of SARS-CoV-2, and similarly found that while cortical neurons and astrocytes are relatively resistant to infection, there was productive infection in choroid plexus organoids 94 .…”

Section: Models For Sars-cov-2 Infectionmentioning

confidence: 99%