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

Nature neuroscience, 2021-11, Vol.24 (11), p.1522 [Peer Reviewed Journal]

2021. The Author(s). ;EISSN: 1546-1726 ;DOI: 10.1038/s41593-021-00926-1 ;PMID: 34675436

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Title:
The SARS-CoV-2 main protease M pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
Author: Wenzel, Jan ; Lampe, Josephine ; Müller-Fielitz, Helge ; Schuster, Raphael ; Zille, Marietta ; Müller, Kristin ; Krohn, Markus ; Körbelin, Jakob ; Zhang, Linlin ; Özorhan, Ümit ; Neve, Vanessa ; Wagner, Julian U G ; Bojkova, Denisa ; Shumliakivska, Mariana ; Jiang, Yun ; Fähnrich, Anke ; Ott, Fabian ; Sencio, Valentin ; Robil, Cyril ; Pfefferle, Susanne ; Sauve, Florent ; Coêlho, Caio Fernando Ferreira ; Franz, Jonas ; Spiecker, Frauke ; Lembrich, Beate ; Binder, Sonja ; Feller, Nina ; König, Peter ; Busch, Hauke ; Collin, Ludovic ; Villaseñor, Roberto ; Jöhren, Olaf ; Altmeppen, Hermann C ; Pasparakis, Manolis ; Dimmeler, Stefanie ; Cinatl, Jindrich ; Püschel, Klaus ; Zelic, Matija ; Ofengeim, Dimitry ; Stadelmann, Christine ; Trottein, François ; Nogueiras, Ruben ; Hilgenfeld, Rolf ; Glatzel, Markus ; Prevot, Vincent ; Schwaninger, Markus
Subjects: Animals ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - pathology ; Brain - metabolism ; Brain - pathology ; Chlorocebus aethiops ; Coronavirus 3C Proteases - genetics ; Coronavirus 3C Proteases - metabolism ; Cricetinae ; Female ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Male ; Mesocricetus ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microvessels - metabolism ; Microvessels - pathology ; SARS-CoV-2 - genetics ; SARS-CoV-2 - metabolism ; Vero Cells
Is Part Of: Nature neuroscience, 2021-11, Vol.24 (11), p.1522
Description: 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 ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M 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 -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
Publisher: United States
Language: English
Identifier: EISSN: 1546-1726
DOI: 10.1038/s41593-021-00926-1
PMID: 34675436
Source: ProQuest One Psychology
MEDLINE
ProQuest Central

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

2021. The Author(s). ;EISSN: 1546-1726 ;DOI: 10.1038/s41593-021-00926-1 ;PMID: 34675436

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