MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Cell Stem Cell. 2020 Dec 3;27(6):951-961.e5. doi: 10.1016/j.stem.2020.10.001. Epub 2020 Oct 13.
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, leads to respiratory symptoms that can be fatal. However, neurological symptoms have also been observed in some patients. The cause of these complications is currently unknown. Here, we use human-pluripotent-stem-cell-derived brain organoids to examine SARS-CoV-2 neurotropism. We find expression of viral receptor ACE2 in mature choroid plexus cells expressing abundant lipoproteins, but not in neurons or other cell types. We challenge organoids with SARS-CoV-2 spike pseudovirus and live virus to demonstrate viral tropism for choroid plexus epithelial cells but little to no infection of neurons or glia. We find that infected cells are apolipoprotein- and ACE2-expressing cells of the choroid plexus epithelial barrier. Finally, we show that infection with SARS-CoV-2 damages the choroid plexus epithelium, leading to leakage across this important barrier that normally prevents entry of pathogens, immune cells, and cytokines into cerebrospinal fluid and the brain.
新型冠状病毒病（COVID-19）是由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）病毒引起的，可导致呼吸症状，严重者可致命。然而，一些患者也出现了神经系统症状。目前尚不清楚这些并发症的原因。在这里，我们使用人多能干细胞衍生的脑类器官来研究 SARS-CoV-2 的嗜神经性。我们发现病毒受体 ACE2 在表达大量脂蛋白的成熟脉络丛细胞中有表达，但在神经元或其他细胞类型中没有表达。我们用 SARS-CoV-2 刺突假病毒和活病毒来挑战类器官，证明了病毒对脉络丛上皮细胞的嗜性，但对神经元或神经胶质细胞的感染很少。我们发现感染的细胞是脉络丛上皮屏障中表达载脂蛋白和 ACE2 的细胞。最后，我们证明了 SARS-CoV-2 的感染会损害脉络丛上皮，导致这个重要屏障的通透性增加，正常情况下该屏障可防止病原体、免疫细胞和细胞因子进入脑脊液和大脑。
