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Nature neuroscience
11, 2021;24 (11): 1522-1533.

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

Jan Wenzel, Josephine Lampe, Helge Müller-Fielitz, Raphael Schuster, Marietta Zille, Kristin Müller, Markus Krohn, Jakob Körbelin, Linlin Zhang, Ümit Özorhan, Vanessa Neve, Julian U G Wagner, Denisa Bojkova, Mariana Shumliakivska, Yun Jiang, Anke Fähnrich, Fabian Ott, Valentin Sencio, Cyril Robil, Susanne Pfefferle, Florent Sauve, Caio Fernando Ferreira Coêlho, Jonas Franz, Frauke Spiecker, Beate Lembrich, Sonja Binder, Nina Feller, Peter König, Hauke Busch, Ludovic Collin, Roberto Villaseñor, Olaf Jöhren, Hermann C Altmeppen, Manolis Pasparakis, Stefanie Dimmeler, Jindrich Cinatl, Klaus Püschel, Matija Zelic, Dimitry Ofengeim, Christine Stadelmann, François Trottein, Ruben Nogueiras, Rolf Hilgenfeld, Markus Glatzel, Vincent Prevot, Markus Schwaninger
Author Information
  1. Jan Wenzel: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  2. Josephine Lampe: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  3. Helge Müller-Fielitz: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  4. Raphael Schuster: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  5. Marietta Zille: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  6. Kristin Müller: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  7. Markus Krohn: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  8. Jakob Körbelin: Department of Oncology, Hematology & Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
  9. Linlin Zhang: Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.
  10. Ümit Özorhan: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  11. Vanessa Neve: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  12. Julian U G Wagner: DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany.
  13. Denisa Bojkova: Institute of Medical Virology, University Frankfurt, Frankfurt, Germany.
  14. Mariana Shumliakivska: Institute for Cardiovascular Regeneration, Cardiopulmonary Institute (CPI), University Frankfurt, Frankfurt, Germany.
  15. Yun Jiang: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  16. Anke Fähnrich: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
  17. Fabian Ott: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
  18. Valentin Sencio: Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France. ORCID
  19. Cyril Robil: Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France. ORCID
  20. Susanne Pfefferle: Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
  21. Florent Sauve: Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, DISTALZ, EGID, Lille, France.
  22. Caio Fernando Ferreira Coêlho: Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, DISTALZ, EGID, Lille, France.
  23. Jonas Franz: Institute of Neuropathology, University Medical Center, Göttingen, Germany. ORCID
  24. Frauke Spiecker: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  25. Beate Lembrich: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  26. Sonja Binder: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  27. Nina Feller: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  28. Peter König: Airway Research Center North, Member of the German Center for Lung Research (DZL), Lübeck, Germany.
  29. Hauke Busch: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
  30. Ludovic Collin: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland.
  31. Roberto Villaseñor: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland.
  32. Olaf Jöhren: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany. ORCID
  33. Hermann C Altmeppen: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
  34. Manolis Pasparakis: Institute for Genetics, University of Cologne, Cologne, Germany. ORCID
  35. Stefanie Dimmeler: DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel and Frankfurt, Germany.
  36. Jindrich Cinatl: Institute of Medical Virology, University Frankfurt, Frankfurt, Germany.
  37. Klaus Püschel: Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  38. Matija Zelic: Rare and Neurologic Diseases Research, Sanofi, Framingham, MA, USA.
  39. Dimitry Ofengeim: Rare and Neurologic Diseases Research, Sanofi, Framingham, MA, USA.
  40. Christine Stadelmann: Institute of Neuropathology, University Medical Center, Göttingen, Germany.
  41. François Trottein: Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France.
  42. Ruben Nogueiras: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain. ORCID
  43. Rolf Hilgenfeld: Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.
  44. Markus Glatzel: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
  45. Vincent Prevot: Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, DISTALZ, EGID, Lille, France. ORCID
  46. Markus Schwaninger: 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. ORCID
PMID: 34675436 DOI: 10.1038/s41593-021-00926-1

Abstract

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.

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Grants

  1. 810331/European Research Council

MeSH Term

Animals
Blood-Brain Barrier
Brain
Chlorocebus aethiops
Coronavirus 3C Proteases
Cricetinae
Female
Humans
Intracellular Signaling Peptides and Proteins
Male
Mesocricetus
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microvessels
SARS-CoV-2
Vero Cells

Chemicals

Intracellular Signaling Peptides and Proteins
NEMO protein, mouse
Coronavirus 3C Proteases
Journal Article Research Support, Non-U.S. Gov't

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