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SARS-CoV-2 infects epithelial cells of the blood-cerebrospinal fluid barrier rather than endothelial cells or pericytes of the blood-brain barrier

As a consequence of SARS-CoV-2 infection various neurocognitive and neuropsychiatric symptoms can appear, which may persist for several months post infection. However, cell type-specific routes of brain infection and underlying mechanisms resulting in neuroglial dysfunction are not well understood....

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Main Authors: Stüdle, Chiara (Author) , Nishihara, Hideaki (Author) , Wischnewski, Sven (Author) , Kulsvehagen, Laila (Author) , Perriot, Sylvain (Author) , Ishikawa, Hiroshi (Author) , Schroten, Horst (Author) , Frank, Stephan (Author) , Deigendesch, Nikolaus (Author) , Du Pasquier, Renaud (Author) , Schirmer, Lucas (Author) , Pröbstel, Anne-Katrin (Author) , Engelhardt, Britta (Author)
Format: Article (Journal)
Language:English
Published: 24 October 2023
In: Fluids and barriers of the CNS
Year: 2023, Volume: 20, Issue: 1, Pages: 1-21
ISSN:2045-8118
DOI:10.1186/s12987-023-00479-4
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1186/s12987-023-00479-4
Verlag, kostenfrei, Volltext: https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-023-00479-4
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Author Notes:Chiara Stüdle, Hideaki Nishihara, Sven Wischnewski, Laila Kulsvehagen, Sylvain Perriot, Hiroshi Ishikawa, Horst Schroten, Stephan Frank, Nikolaus Deigendesch, Renaud Du Pasquier, Lucas Schirmer, Anne-Katrin Pröbstel and Britta Engelhardt
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Summary:As a consequence of SARS-CoV-2 infection various neurocognitive and neuropsychiatric symptoms can appear, which may persist for several months post infection. However, cell type-specific routes of brain infection and underlying mechanisms resulting in neuroglial dysfunction are not well understood. Here, we investigated the susceptibility of cells constituting the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP) to SARS-CoV-2 infection using human induced pluripotent stem cell (hiPSC)-derived cellular models and a ChP papilloma-derived epithelial cell line as well as ChP tissue from COVID-19 patients, respectively. We noted a differential infectibility of hiPSC-derived brain microvascular endothelial cells (BMECs) depending on the differentiation method. Extended endothelial culture method (EECM)-BMECs characterized by a complete set of endothelial markers, good barrier properties and a mature immune phenotype were refractory to SARS-CoV-2 infection and did not exhibit an activated phenotype after prolonged SARS-CoV-2 inoculation. In contrast, defined medium method (DMM)-BMECs, characterized by a mixed endothelial and epithelial phenotype and excellent barrier properties were productively infected by SARS-CoV-2 in an ACE2-dependent manner. hiPSC-derived brain pericyte-like cells (BPLCs) lacking ACE2 expression were not susceptible to SARS-CoV-2 infection. Furthermore, the human choroid plexus papilloma-derived epithelial cell line HIBCPP, modeling the BCSFB was productively infected by SARS-CoV-2 preferentially from the basolateral side, facing the blood compartment. Assessment of ChP tissue from COVID-19 patients by RNA in situ hybridization revealed SARS-CoV-2 transcripts in ChP epithelial and ChP stromal cells. Our study shows that the BCSFB of the ChP rather than the BBB is susceptible to direct SARS-CoV-2 infection. Thus, neuropsychiatric symptoms because of COVID-19 may rather be associated with dysfunction of the BCSFB than the BBB. Future studies should consider a role of the ChP in underlying neuropsychiatric symptoms following SARS-CoV-2 infection.
Item Description:Gesehen am 22.07.2024
Physical Description:Online Resource
ISSN:2045-8118
DOI:10.1186/s12987-023-00479-4

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