{Reference Type}: Journal Article
{Title}: Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2.
{Author}: Shaker MR;Slonchak A;Al-Mhanawi B;Morrison SD;Sng JDJ;Cooper-White J;Khromykh AA;Wolvetang EJ;
{Journal}: Sci Adv
{Volume}: 10
{Issue}: 23
{Year}: 2024 Jun 7
{Factor}: 14.957
{DOI}: 10.1126/sciadv.adj4735
{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.