01791nas a2200217   4500000000100000008004100001260001500042100002300057700002000080700002100100700002100121700002100142700002400163700002600187700002300213245009500236856005500331300001300386490000700399520116700406       2024                            d  c2024-06-051 aMohammed R. Shaker1 aAndrii Slonchak1 aBahaa Al-mhanawi1 aSean D. Morrison1 aJulian D. J. Sng1 aJustin Cooper-White1 aAlexander A. Khromykh1 aErnst J. Wolvetang00aChoroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2  uhttps://www.science.org/doi/10.1126/sciadv.adj4735  aeadj47350 v103 aWhy 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.