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

• Published in: Fluids and barriers of the CNS Vol. 20; no. 1; pp. 76 - 21
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24.10.2023; BioMed Central; BMC
• Subjects: ACE2; Amino acids; Analysis; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-cerebrospinal fluid barrier; Brain; Cell culture; Cell differentiation; Cerebrospinal fluid; Choroid plexus; Choroid Plexus - metabolism; Choroid plexus epithelial cells; Cogeneration power plants; Cognition; COVID-19; Diagnostic reagents industry; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Epithelial cells; Epithelial Cells - metabolism; Ethylenediaminetetraacetic acid; Growth factors; Health aspects; hiPSC-derived brain microvascular endothelial cells; Humans; Hybridization; Induced Pluripotent Stem Cells - metabolism; Infection; Infections; Inoculation; Mental disorders; Microvasculature; Papilloma; Penicillin; Pericytes; Pericytes - metabolism; Phenotypes; Pluripotency; RNA; SARS-CoV-2; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Stem cells; Stromal cells; Canada; Choroid plexus epithelial cells; SARS-CoV-2; Blood-cerebrospinal fluid barrier; Blood-brain barrier; hiPSC-derived brain microvascular endothelial cells
• ISSN: 2045-8118; 2045-8118
• DOI: 10.1186/s12987-023-00479-4

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.