Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium

Neurological complications are common in patients with COVID-19. While SARS-CoV-2, the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function are not well understood, and experimental models using human brain cells are urgently needed. Here we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found modest numbers of infected neurons and astrocytes, but greater infection of choroid plexus epithelial cells. We optimized a protocol to generate choroid plexus organoids from hiPSCs, which revealed productive SARS-CoV-2 infection that leads to increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our results provide evidence for SARS-CoV-2 neurotropism and support use of hiPSC-derived brain organoids as a platform to investigate the cellular susceptibility, disease mechanisms, and treatment strategies for SARS-CoV-2 infection.

新型冠状病毒肺炎（COVID-19）患者常出现神经系统并发症。作为COVID-19的致病原，严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）已在部分患者的脑组织中被检出，但其感染脑细胞并影响其功能的机制尚未完全阐明，因此亟需建立基于人类脑细胞的实验模型。本研究探究了人类诱导多能干细胞（human induced pluripotent stem cell, hiPSC）衍生的单层脑细胞及区域特异性脑类器官对SARS-CoV-2感染的易感性。研究发现，受感染的神经元与星形胶质细胞数量较少，但脉络丛上皮细胞的感染率更高。我们优化了一套从hiPSCs中培养脉络丛类器官的实验方案，结果显示SARS-CoV-2可在其中实现增殖性感染，并引发细胞死亡增加及转录失调，后者提示存在炎症反应与细胞功能缺陷。综上，本研究结果为SARS-CoV-2的嗜神经性提供了实验证据，并支持将hiPSC衍生的脑类器官作为研究SARS-CoV-2感染的细胞易感性、疾病机制及治疗策略的实验平台。