Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2.
Sci Adv
; 10(23): eadj4735, 2024 Jun 07.
Article
in En
| MEDLINE
| ID: mdl-38838150
ABSTRACT
Why individuals with Down syndrome (DS) are more susceptible to SARS-CoV-2-induced neuropathology remains elusive. Choroid plexus (ChP) plays critical roles in barrier function and immune response modulation and expresses the ACE2 receptor and the chromosome 21-encoded TMPRSS2 protease, suggesting its substantial role in establishing SARS-CoV-2 infection in the brain. To explore this, we established brain organoids from DS and isogenic euploid iPSC that consist of a core of functional cortical neurons surrounded by a functional ChP-like epithelium (ChPCOs). DS-ChPCOs recapitulated abnormal DS cortical development and revealed defects in ciliogenesis and epithelial cell polarity in ChP-like epithelium. We then demonstrated that the ChP-like epithelium facilitates infection and replication of SARS-CoV-2 in cortical neurons and that this is increased in DS. Inhibiting TMPRSS2 and furin activity reduced viral replication in DS-ChPCOs to euploid levels. This model enables dissection of the role of ChP in neurotropic virus infection and euploid forebrain development and permits screening of therapeutics for SARS-CoV-2-induced neuropathogenesis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Serine Endopeptidases
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Organoids
/
Choroid Plexus
/
Down Syndrome
/
SARS-CoV-2
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COVID-19
Limits:
Humans
Language:
En
Journal:
Sci Adv
Year:
2024
Document type:
Article