ABSTRACT
Background: Several lines of evidence suggest that neurological symptoms in patients suffering from Coronavirus disease 2019 (COVID-19) occur partially due to damage to small vessels in the brain. However, the potential mechanisms underlying this pathology are unclear. Aim: Here, we describe a novel pathway by which SARSCoV- 2 affects the brain vasculature and thereby potentially induces neurocognitive impairment in patients. Method: We examined brain tissue of deceased COVID- 19 patients and different animal models of this disease for microvascular pathology. Using several techniques like mass spectrometry, high resolution microscopy, transgenic animals, and AAV-mediated gene transfer, we investigated the effect of the SARS-CoV-2 main protease (Mpro) on brain endothelial cells. Results/Conclusions: In brains of 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 Mpro cleaves NEMO, the essential modulator of nuclear factor-jB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of RIPK3, 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 Mpro-induced microvascular pathology. These data suggest a novel mechanism by which SARS-CoV-2 affects the brain vasculature and a potential therapeutic option to interfere with the neurological consequences of COVID-19.