Stüdle, Chiara; Nishihara, Hideaki; Wischnewski, Sven; Kulsvehagen, Laila; Perriot, Sylvain; Ishikawa, Hiroshi; Schroten, Horst; Frank, Stephan; Deigendesch, Nikolaus; Du Pasquier, Renaud; Schirmer, Lucas; Pröbstel, Anne-Katrin; Engelhardt, Britta (2023). SARS-CoV-2 infects epithelial cells of the blood-cerebrospinal fluid barrier rather than endothelial cells or pericytes of the blood-brain barrier. Fluids and barriers of the CNS, 20(1), p. 76. BioMed Central 10.1186/s12987-023-00479-4
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BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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 Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute |
UniBE Contributor: |
Stüdle, Chiara, Nishihara, Hideaki, Engelhardt, Britta |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2045-8118 |
Publisher: |
BioMed Central |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
25 Oct 2023 10:16 |
Last Modified: |
29 Oct 2023 02:26 |
Publisher DOI: |
10.1186/s12987-023-00479-4 |
PubMed ID: |
37875964 |
Uncontrolled Keywords: |
Blood-brain barrier Blood-cerebrospinal fluid barrier Choroid plexus epithelial cells SARS-CoV-2 hiPSC-derived brain microvascular endothelial cells |
BORIS DOI: |
10.48350/187432 |
URI: |
https://boris.unibe.ch/id/eprint/187432 |
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