The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
Jan Wenzel
(1, 2)
,
Josephine Lampe
(1, 2)
,
Helge Müller-Fielitz
(1)
,
Raphael Schuster
(1)
,
Marietta Zille
(1, 2)
,
Kristin Müller
(1)
,
Markus Krohn
(1, 2)
,
Jakob Körbelin
(3)
,
Linlin Zhang
(1, 4)
,
Ümit Özorhan
(1, 2)
,
Vanessa Neve
(1)
,
Julian Wagner
(5, 2)
,
Denisa Bojkova
(6)
,
Mariana Shumliakivska
(5)
,
Yun Jiang
(1)
,
Anke Fähnrich
(1)
,
Fabian Ott
(1)
,
Valentin Sencio
(7, 8)
,
Cyril Robil
(7, 8)
,
Susanne Pfefferle
(3)
,
Florent Sauve
(9, 8, 10, 11)
,
Caio Fernando Ferreira Coêlho
(9, 8, 10, 11)
,
Jonas Franz
(12, 13, 14)
,
Frauke Spiecker
(1)
,
Beate Lembrich
(1)
,
Sonja Binder
(1)
,
Nina Feller
(1, 2)
,
Peter König
(15, 1)
,
Hauke Busch
(1)
,
Ludovic Collin
(16)
,
Roberto Villaseñor
(16)
,
Olaf Jöhren
(1)
,
Hermann Altmeppen
(3)
,
Manolis Pasparakis
(17)
,
Stefanie Dimmeler
(5, 2)
,
Jindrich Cinatl
(6)
,
Klaus Püschel
(3)
,
Matija Zelic
(18)
,
Dimitry Ofengeim
(18)
,
Christine Stadelmann
(12)
,
François Trottein
(7, 8)
,
Ruben Nogueiras
(19)
,
Rolf Hilgenfeld
(1, 4)
,
Markus Glatzel
(3)
,
Vincent Prevot
(9, 8, 11, 10)
,
Markus Schwaninger
(1, 2)
1
Universität zu Lübeck = University of Lübeck [Lübeck]
2 DZHK - German Center for Cardiovascular Research
3 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
4 DZIF - German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems
5 Centre for Molecular Medicine - Institute of Cardiovascular Regeneration [Frankfurt, Germany]
6 Frankfurt University Hospital
7 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
8 CHU Lille
9 LilNCog - Lille Neurosciences & Cognition - U 1172
10 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
11 Excellence Laboratory LabEx DISTALZ
12 UMG - University Medical Center Göttingen
13 Georg-August-University = Georg-August-Universität Göttingen
14 Max Planck Institute for Experimental Medicine [Göttingen, Germany]
15 German Center for Lung Research
16 pRED - Roche Pharma Research and Early Development [Basel]
17 University of Cologne
18 Sanofi US
19 IDIS - Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela
2 DZHK - German Center for Cardiovascular Research
3 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
4 DZIF - German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems
5 Centre for Molecular Medicine - Institute of Cardiovascular Regeneration [Frankfurt, Germany]
6 Frankfurt University Hospital
7 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
8 CHU Lille
9 LilNCog - Lille Neurosciences & Cognition - U 1172
10 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
11 Excellence Laboratory LabEx DISTALZ
12 UMG - University Medical Center Göttingen
13 Georg-August-University = Georg-August-Universität Göttingen
14 Max Planck Institute for Experimental Medicine [Göttingen, Germany]
15 German Center for Lung Research
16 pRED - Roche Pharma Research and Early Development [Basel]
17 University of Cologne
18 Sanofi US
19 IDIS - Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela
Jan Wenzel
- Function : Author
- PersonId : 1153275
- ORCID : 0000-0001-6313-2439
Helge Müller-Fielitz
- Function : Author
- PersonId : 1152530
- ORCID : 0000-0003-2815-4426
Marietta Zille
- Function : Author
- PersonId : 1153276
- ORCID : 0000-0002-0609-8956
Markus Krohn
- Function : Author
- PersonId : 1153277
- ORCID : 0000-0002-5345-9048
Jakob Körbelin
- Function : Author
- PersonId : 1153278
- ORCID : 0000-0002-5435-7182
Ümit Özorhan
- Function : Author
- PersonId : 1153279
- ORCID : 0000-0002-7661-2818
Yun Jiang
- Function : Author
- PersonId : 1153280
- ORCID : 0000-0002-2886-7373
Valentin Sencio
- Function : Author
- PersonId : 794520
- ORCID : 0000-0002-6379-4317
Cyril Robil
- Function : Author
- PersonId : 809150
- ORCID : 0000-0002-3607-244X
Susanne Pfefferle
- Function : Author
- PersonId : 1153281
- ORCID : 0000-0001-7489-6557
Jonas Franz
- Function : Author
- PersonId : 1153282
- ORCID : 0000-0001-7523-6622
Olaf Jöhren
- Function : Author
- PersonId : 1153283
- ORCID : 0000-0002-0532-5133
Hermann Altmeppen
- Function : Author
- PersonId : 1153284
- ORCID : 0000-0001-9439-6533
Manolis Pasparakis
- Function : Author
- PersonId : 1153285
- ORCID : 0000-0002-9870-0966
Ruben Nogueiras
- Function : Author
- PersonId : 762262
- ORCID : 0000-0002-9976-9930
Markus Glatzel
- Function : Author
- PersonId : 1153286
- ORCID : 0000-0002-7720-8817
- IdRef : 165439505
Vincent Prevot
- Function : Author
- PersonId : 760908
- ORCID : 0000-0001-7185-3615
- IdRef : 076189279
Markus Schwaninger
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 786247
- ORCID : 0000-0002-4510-9718
- IdRef : 171622936
Connectez-vous pour contacter l'auteur
Abstract
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-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.
Domains
Life Sciences [q-bio]
Origin : Publication funded by an institution