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.

据报道，SARS-CoV-2 具有侵入人类和模型动物大脑的能力。然而，目前尚不清楚 SARS-CoV-2 是否以及如何穿过血脑屏障 (BBB)。在此，偶尔在受感染的 K18-hACE2 转基因小鼠的血管壁和血管周围空间以及脑微血管内皮细胞 (BMEC) 中检测到 SARS-CoV-2 RNA。此外，受感染血管的渗透性增加。此外，通过施用伊文思蓝，在受感染的仓鼠中发现了 BBB 的解体。有趣的是，claudin5、ZO-1、occludin 和紧密连接 (TJ) 的超微结构的表达没有变化，而基膜在感染动物中被破坏。使用包含具有星形胶质细胞的原代 BMEC 的体外 BBB 模型，发现 SARS-CoV-2 感染并穿过 BMEC。与体内实验一致，在 SARS-CoV-2 感染的 BMEC 中，MMP9 的表达增加，胶原蛋白 IV 减少，而 TJ 的标记物没有改变。此外，SARS-CoV-2感染后发生了炎症反应，包括血管炎、神经胶质激活和炎症因子上调。总体而言，我们的结果提供证据支持 SARS-CoV-2 可以通过跨细胞途径穿过 BBB，同时基底膜被破坏而 TJ 没有明显改变。SARS-CoV-2 感染后炎症因子上调。总体而言，我们的结果提供证据支持 SARS-CoV-2 可以通过跨细胞途径穿过 BBB，同时基底膜被破坏而 TJ 没有明显改变。SARS-CoV-2 感染后炎症因子上调。总体而言，我们的结果提供证据支持 SARS-CoV-2 可以通过跨细胞途径穿过 BBB，同时基底膜被破坏而 TJ 没有明显改变。