دورية أكاديمية
The SARS-CoV-2 main protease M pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.
العنوان: | The SARS-CoV-2 main protease M pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. |
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المؤلفون: | Wenzel J; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany., Lampe J; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany., Müller-Fielitz H; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Schuster R; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Zille M; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany., Müller K; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Krohn M; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany., Körbelin J; Department of Oncology, Hematology & Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Zhang L; Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.; German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, Lübeck, Germany., Özorhan Ü; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany., Neve V; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Wagner JUG; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany.; Institute for Cardiovascular Regeneration, Cardiopulmonary Institute (CPI), University Frankfurt, Frankfurt, Germany., Bojkova D; Institute of Medical Virology, University Frankfurt, Frankfurt, Germany., Shumliakivska M; Institute for Cardiovascular Regeneration, Cardiopulmonary Institute (CPI), University Frankfurt, Frankfurt, Germany., Jiang Y; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Fähnrich A; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany., Ott F; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany., Sencio V; Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France., Robil C; Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France., Pfefferle S; Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Sauve F; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, DISTALZ, EGID, Lille, France., Coêlho CFF; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, DISTALZ, EGID, Lille, France., Franz J; Institute of Neuropathology, University Medical Center, Göttingen, Germany.; Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany.; Max Planck Institute for Experimental Medicine, Göttingen, Germany., Spiecker F; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Lembrich B; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Binder S; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Feller N; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany., König P; Airway Research Center North, Member of the German Center for Lung Research (DZL), Lübeck, Germany.; Institute of Anatomy, University of Lübeck, Lübeck, Germany., Busch H; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany., Collin L; Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland., Villaseñor R; Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland., Jöhren O; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Altmeppen HC; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Pasparakis M; Institute for Genetics, University of Cologne, Cologne, Germany., Dimmeler S; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany.; Institute for Cardiovascular Regeneration, Cardiopulmonary Institute (CPI), University Frankfurt, Frankfurt, Germany., Cinatl J; Institute of Medical Virology, University Frankfurt, Frankfurt, Germany., Püschel K; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Zelic M; Rare and Neurologic Diseases Research, Sanofi, Framingham, MA, USA., Ofengeim D; Rare and Neurologic Diseases Research, Sanofi, Framingham, MA, USA., Stadelmann C; Institute of Neuropathology, University Medical Center, Göttingen, Germany., Trottein F; Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France., Nogueiras R; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain., Hilgenfeld R; Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.; German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, Lübeck, Germany., Glatzel M; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Prevot V; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, DISTALZ, EGID, Lille, France., Schwaninger M; Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. markus.schwaninger@uni-luebeck.de.; DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany. markus.schwaninger@uni-luebeck.de. |
المصدر: | Nature neuroscience [Nat Neurosci] 2021 Nov; Vol. 24 (11), pp. 1522-1533. Date of Electronic Publication: 2021 Oct 21. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE |
أسماء مطبوعة: | Publication: <2002->: New York, NY : Nature Publishing Group Original Publication: New York, NY : Nature America Inc., c1998- |
مواضيع طبية MeSH: | Blood-Brain Barrier/*metabolism , Brain/*metabolism , Coronavirus 3C Proteases/*metabolism , Intracellular Signaling Peptides and Proteins/*metabolism , Microvessels/*metabolism , SARS-CoV-2/*metabolism, Animals ; Blood-Brain Barrier/pathology ; Brain/pathology ; Chlorocebus aethiops ; Coronavirus 3C Proteases/genetics ; Cricetinae ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Male ; Mesocricetus ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microvessels/pathology ; SARS-CoV-2/genetics ; Vero Cells |
مستخلص: | 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-κB. 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. (© 2021. The Author(s).) |
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معلومات مُعتمدة: | 810331 International ERC_ European Research Council |
المشرفين على المادة: | 0 (Intracellular Signaling Peptides and Proteins) 0 (NEMO protein, mouse) EC 3.4.22.28 (Coronavirus 3C Proteases) |
تواريخ الأحداث: | Date Created: 20211022 Date Completed: 20211108 Latest Revision: 20230207 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC8553622 |
DOI: | 10.1038/s41593-021-00926-1 |
PMID: | 34675436 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1546-1726 |
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DOI: | 10.1038/s41593-021-00926-1 |