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Publication : The SARS-CoV-2 main protease M<sup>pro</sup> causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

First Author  Wenzel J Year  2021
Journal  Nat Neurosci Volume  24
Issue  11 Pages  1522-1533
PubMed ID  34675436 Mgi Jnum  J:323957
Mgi Id  MGI:7263135 Doi  10.1038/s41593-021-00926-1
Citation  Wenzel J, et al. (2021) The SARS-CoV-2 main protease M(pro) causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat Neurosci 24(11):1522-1533
abstractText  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-kappaB. 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.
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