SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration

封堵器 紧密连接 基底膜 血脑屏障 细胞生物学 体内 MMP9公司 病理 生物 免疫学 医学 下调和上调 中枢神经系统 神经科学 生物化学 生物技术 基因
作者
Ling Zhang,Li Zhou,Linlin Bao,Jiangning Liu,Huachen Zhu,Qi Lv,Ruixue Liu,Wei Chen,Wei Tong,Qiang Wei,Yanfeng Xu,Wei Deng,Hong Gao,Jing Xue,Zhiqi Song,Pin Yü,Yunlin Han,Yu Zhang,Xiuping Sun,Xuan Yu,Chuan Qin
出处
期刊:Signal Transduction and Targeted Therapy [Springer Nature]
卷期号:6 (1) 被引量:218
标识
DOI:10.1038/s41392-021-00719-9
摘要

Abstract SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood–brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.
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