%0 Journal Article
%T Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2.
%A Shaker MR
%A Slonchak A
%A Al-Mhanawi B
%A Morrison SD
%A Sng JDJ
%A Cooper-White J
%A Khromykh AA
%A Wolvetang EJ
%J Sci Adv
%V 10
%N 23
%D 2024 Jun 7
%M 38838150
%F 14.957
%R 10.1126/sciadv.adj4735
%X 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.