Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M^pro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M^pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M^pro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

2019 年冠状病毒病 (COVID-19) 可损害大脑小血管并引起神经系统症状。在这里，我们描述了 COVID-19 患者脑小血管的结构变化，并阐明了血管病理学的潜在机制。在严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 感染者和动物模型的大脑中，我们发现越来越多的空基底膜管，即所谓的弦状血管，代表毛细血管丢失的残余物。我们获得了脑内皮细胞被感染的证据，并且 SARS-CoV-2 (M ^pro ) 的主要蛋白酶会切割核因子-κB 的基本调节剂 NEMO。通过消融 NEMO，M ^pro诱导人脑内皮细胞死亡和小鼠弦状血管的发生。受体相互作用蛋白激酶 (RIPK) 3（调节细胞死亡的介质）的缺失可阻止血管稀疏和因 NEMO 消融引起的血脑屏障破坏。重要的是，RIPK 信号转导的药理学抑制剂阻止了 M ^pro诱导的微血管病变。我们的数据表明 RIPK 是治疗 COVID-19 神经病理学的潜在治疗靶点。