Wenzel, Jan ORCID: 0000-0001-6313-2439, Lampe, Josephine, Mueller-Fielitz, Helge, Schuster, Raphael, Zille, Marietta ORCID: 0000-0002-0609-8956, Mueller, Kristin, Krohn, Markus ORCID: 0000-0002-5345-9048, Koerbelin, Jakob, Zhang, Linlin, Ozorhan, Umit, Neve, Vanessa, Wagner, Julian U. G., Bojkova, Denisa, Shumliakivska, Mariana, Jiang, Yun ORCID: 0000-0002-2886-7373, Faehnrich, Anke, Ott, Fabian, Sencio, Valentin, Robil, Cyril, Pfefferle, Susanne, Sauve, Florent, Coelho, Caio Fernando Ferreira, Franz, Jonas ORCID: 0000-0001-7523-6622, Spiecker, Frauke, Lembrich, Beate, Binder, Sonja, Feller, Nina, Koenig, Peter, Busch, Hauke, Collin, Ludovic, Villasenor, Roberto, Joehren, Olaf, Altmeppen, Hermann C., Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Dimmeler, Stefanie, Cinatl, Jindrich, Pueschel, Klaus, Zelic, Matija, Ofengeim, Dimitry, Stadelmann, Christine, Trottein, Francois, Nogueiras, Ruben, Hilgenfeld, Rolf, Glatzel, Markus, Prevot, Vincent and Schwaninger, Markus (2021). The SARS-CoV-2 main protease M-pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat. Neurosci., 24 (11). S. 1522 - 1534. BERLIN: NATURE PORTFOLIO. ISSN 1546-1726

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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-pro) cleaves NEMO, the essential modulator of nuclear factor-kappa B. 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. A novel study led by scientists in Lubeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M-pro, potentially causing cerebral COVID-19 and 'long COVID' symptoms.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wenzel, JanUNSPECIFIEDorcid.org/0000-0001-6313-2439UNSPECIFIED
Lampe, JosephineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller-Fielitz, HelgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuster, RaphaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zille, MariettaUNSPECIFIEDorcid.org/0000-0002-0609-8956UNSPECIFIED
Mueller, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krohn, MarkusUNSPECIFIEDorcid.org/0000-0002-5345-9048UNSPECIFIED
Koerbelin, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, LinlinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozorhan, UmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neve, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, Julian U. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojkova, DenisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shumliakivska, MarianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiang, YunUNSPECIFIEDorcid.org/0000-0002-2886-7373UNSPECIFIED
Faehnrich, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ott, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sencio, ValentinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robil, CyrilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfefferle, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauve, FlorentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coelho, Caio Fernando FerreiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franz, JonasUNSPECIFIEDorcid.org/0000-0001-7523-6622UNSPECIFIED
Spiecker, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lembrich, BeateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binder, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feller, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busch, HaukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collin, LudovicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villasenor, RobertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joehren, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmeppen, Hermann C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Dimmeler, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cinatl, JindrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pueschel, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zelic, MatijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ofengeim, DimitryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stadelmann, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trottein, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogueiras, RubenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilgenfeld, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glatzel, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prevot, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwaninger, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-604150
DOI: 10.1038/s41593-021-00926-1
Journal or Publication Title: Nat. Neurosci.
Volume: 24
Number: 11
Page Range: S. 1522 - 1534
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1546-1726
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NF-KAPPA-B; COVID-19; MODEL; INHIBITION; INFECTION; NECROSIS; GAMMA; TAK1; MICE; ACE2Multiple languages
NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60415

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