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Journal Article Ppublish 12 citations

PubMed: 38838150 DOI: 10.1126/sciadv.adj4735

Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2.

Sci Adv 10(23):eadj4735

Authors: Mohammed R Shaker, Andrii Slonchak, Bahaa Al-Mhanawi, Sean D Morrison, Julian D J Sng, Justin Cooper-White, Alexander A Khromykh, Ernst J Wolvetang

Affiliations

  • Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • UQ Centre in Stem Cell Engineering and Regenerative Engineering (UQ StemCARE), The University of Queensland, Brisbane, Queensland 4072, Australia.
  • School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
  • School of Chemical Engineering, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • GVN Centre of Excellence, Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia.

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.

MeSH

Sars-Cov-2, Down Syndrome, Neurons, Biological Science Disciplines, Brain, Organoids, Covid-19, Severe Acute Respiratory Syndrome-Related Coronavirus, Choroid Plexus, Epithelium, Infections

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