The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

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-kappa B. 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. A novel study led by scientists in Lubeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M-pro, potentially causing cerebral COVID-19 and 'long COVID' symptoms.

Automated summary

COVID-19 can cause damage to cerebral small vessels and neurological symptoms by infecting brain endothelial cells and cleaving NEMO through the viral protease M-pro. In animal models, the loss of NEMO leads to the generation of string vessels. Blocking RIPK3, a mediator of regulated cell death, can prevent vessel disruption caused by NEMO ablation, suggesting it as a potential therapeutic target.