The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
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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
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- Function : Correspondent author
- PersonId : 786247
- ORCID : 0000-0002-4510-9718
- IdRef : 171622936
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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