The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
2021 | journal article. A publication with affiliation to the University of Göttingen.
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The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
Wenzel, J.; Lampe, J.; Müller-Fielitz, H.; Schuster, R.; Zille, M.; Müller, K. & Krohn, M. et al. (2021)
Nature Neuroscience, 24(11) pp. 1522-1533. DOI: https://doi.org/10.1038/s41593-021-00926-1
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Details
- Authors
- Wenzel, Jan; Lampe, Josephine; Müller-Fielitz, Helge; Schuster, Raphael; Zille, Marietta; Müller, Kristin; Krohn, Markus; Körbelin, Jakob; Zhang, Linlin; Özorhan, Ümit; Schwaninger, Markus
- 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.
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. - Issue Date
- 2021
- Journal
- Nature Neuroscience
- Project
- TRR 274: Checkpoints of Central Nervous System Recovery
TRR 274 | B01: The role of inflammatory cytokine signaling for efficient remyelination in multiple sclerosis - Working Group
- RG Stadelmann-Nessler
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Language
- English