Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2.
Mohammed R ShakerAndrii SlonchakBahaa Al-MhanawiSean D MorrisonJulian D J SngJustin John Cooper-WhiteAlexander A KhromykhErnst J WolvetangPublished in: Science advances (2024)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- resting state
- immune response
- white matter
- high glucose
- diabetic rats
- functional connectivity
- spinal cord
- cerebral ischemia
- drug induced
- signaling pathway
- dendritic cells
- angiotensin ii
- dna methylation
- single cell
- gene expression
- spinal cord injury
- brain injury
- genome wide
- angiotensin converting enzyme
- copy number
- subarachnoid hemorrhage
- stress induced