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

Autor: Jan Wenzel, Julian U. G. Wagner, Cyril Robil, Peter König, Rolf Hilgenfeld, Beate Lembrich, Christine Stadelmann, Jonas Franz, Denisa Bojkova, Helge Müller-Fielitz, Valentin Sencio, Yun Jiang, François Trottein, Dimitry Ofengeim, Susanne Pfefferle, Kristin Müller, Markus Glatzel, Roberto Villaseñor, Matija Zelic, Markus Krohn, Fabian Ott, Hauke Busch, Frauke Spiecker, Anke Fähnrich, Ludovic Collin, Caio Coelho, Vincent Prevot, Jakob Körbelin, Josephine Lampe, Mariana Shumliakivska, Umit Ozorhan, Stefanie Dimmeler, Klaus Püschel, Jindrich Cinatl, Hermann C. Altmeppen, Rubén Nogueiras, Olaf Jöhren, Florent Sauve, Vanessa Neve, Raphael Schuster, Sonja Binder, Linlin Zhang, Manolis Pasparakis, Markus Schwaninger, Nina Feller, Marietta Zille
Přispěvatelé: TROTTEIN, François, Universität zu Lübeck = University of Lübeck [Lübeck], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), Institute of Cardiovascular Regeneration [Frankfurt, Germany] (Centre for Molecular Medicine), Goethe-University Frankfurt am Main, Frankfurt University Hospital, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Excellence Laboratory LabEx DISTALZ, University Medical Center Göttingen (UMG), Georg-August-University = Georg-August-Universität Göttingen, Max Planck Institute for Experimental Medicine [Göttingen, Germany], German Center for Lung Research, Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], University of Cologne, Sanofi US, Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela (IDIS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Nature Neuroscience
Nature Neuroscience, 2021, 24 (11), pp.1522-1533. ⟨10.1038/s41593-021-00926-1⟩
ISSN: 1097-6256
1546-1726
Popis: 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 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro 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 Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
Databáze: OpenAIRE
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