tetano
Editor, Senior Moderator
Nat Neurosci
. 2021 Oct 21.
doi: 10.1038/s41593-021-00926-1. Online ahead of print.
The SARS-CoV-2 main protease M [SUP]pro[/SUP] causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
Jan Wenzel[SUP] #[/SUP][SUP] 1 2 [/SUP], Josephine Lampe[SUP] #[/SUP][SUP] 1 2 [/SUP], Helge Müller-Fielitz[SUP] #[/SUP][SUP] 1 [/SUP], Raphael Schuster[SUP] 1 [/SUP], Marietta Zille[SUP] 1 2 [/SUP], Kristin Müller[SUP] 1 [/SUP], Markus Krohn[SUP] 1 2 [/SUP], Jakob Körbelin[SUP] 3 [/SUP], Linlin Zhang[SUP] 4 5 [/SUP], Ümit Özorhan[SUP] 1 2 [/SUP], Vanessa Neve[SUP] 1 [/SUP], Julian U G Wagner[SUP] 2 6 [/SUP], Denisa Bojkova[SUP] 7 [/SUP], Mariana Shumliakivska[SUP] 6 [/SUP], Yun Jiang[SUP] 1 [/SUP], Anke Fähnrich[SUP] 8 9 [/SUP], Fabian Ott[SUP] 8 9 [/SUP], Valentin Sencio[SUP] 10 [/SUP], Cyril Robil[SUP] 10 [/SUP], Susanne Pfefferle[SUP] 11 [/SUP], Florent Sauve[SUP] 12 [/SUP], Caio Fernando Ferreira Coêlho[SUP] 12 [/SUP], Jonas Franz[SUP] 13 14 15 [/SUP], Frauke Spiecker[SUP] 1 [/SUP], Beate Lembrich[SUP] 1 [/SUP], Sonja Binder[SUP] 1 [/SUP], Nina Feller[SUP] 1 2 [/SUP], Peter König[SUP] 16 17 [/SUP], Hauke Busch[SUP] 8 9 [/SUP], Ludovic Collin[SUP] 18 [/SUP], Roberto Villaseñor[SUP] 18 [/SUP], Olaf Jöhren[SUP] 1 [/SUP], Hermann C Altmeppen[SUP] 19 [/SUP], Manolis Pasparakis[SUP] 20 [/SUP], Stefanie Dimmeler[SUP] 2 6 [/SUP], Jindrich Cinatl[SUP] 7 [/SUP], Klaus Püschel[SUP] 21 [/SUP], Matija Zelic[SUP] 22 [/SUP], Dimitry Ofengeim[SUP] 22 [/SUP], Christine Stadelmann[SUP] 13 [/SUP], François Trottein[SUP] 10 [/SUP], Ruben Nogueiras[SUP] 23 [/SUP], Rolf Hilgenfeld[SUP] 4 5 [/SUP], Markus Glatzel[SUP] 19 [/SUP], Vincent Prevot[SUP] 12 [/SUP], Markus Schwaninger[SUP] 24 25 [/SUP]
Affiliations
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[SUP]pro[/SUP]) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M[SUP]pro[/SUP] 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[SUP]pro[/SUP]-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
. 2021 Oct 21.
doi: 10.1038/s41593-021-00926-1. Online ahead of print.
The SARS-CoV-2 main protease M [SUP]pro[/SUP] causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
Jan Wenzel[SUP] #[/SUP][SUP] 1 2 [/SUP], Josephine Lampe[SUP] #[/SUP][SUP] 1 2 [/SUP], Helge Müller-Fielitz[SUP] #[/SUP][SUP] 1 [/SUP], Raphael Schuster[SUP] 1 [/SUP], Marietta Zille[SUP] 1 2 [/SUP], Kristin Müller[SUP] 1 [/SUP], Markus Krohn[SUP] 1 2 [/SUP], Jakob Körbelin[SUP] 3 [/SUP], Linlin Zhang[SUP] 4 5 [/SUP], Ümit Özorhan[SUP] 1 2 [/SUP], Vanessa Neve[SUP] 1 [/SUP], Julian U G Wagner[SUP] 2 6 [/SUP], Denisa Bojkova[SUP] 7 [/SUP], Mariana Shumliakivska[SUP] 6 [/SUP], Yun Jiang[SUP] 1 [/SUP], Anke Fähnrich[SUP] 8 9 [/SUP], Fabian Ott[SUP] 8 9 [/SUP], Valentin Sencio[SUP] 10 [/SUP], Cyril Robil[SUP] 10 [/SUP], Susanne Pfefferle[SUP] 11 [/SUP], Florent Sauve[SUP] 12 [/SUP], Caio Fernando Ferreira Coêlho[SUP] 12 [/SUP], Jonas Franz[SUP] 13 14 15 [/SUP], Frauke Spiecker[SUP] 1 [/SUP], Beate Lembrich[SUP] 1 [/SUP], Sonja Binder[SUP] 1 [/SUP], Nina Feller[SUP] 1 2 [/SUP], Peter König[SUP] 16 17 [/SUP], Hauke Busch[SUP] 8 9 [/SUP], Ludovic Collin[SUP] 18 [/SUP], Roberto Villaseñor[SUP] 18 [/SUP], Olaf Jöhren[SUP] 1 [/SUP], Hermann C Altmeppen[SUP] 19 [/SUP], Manolis Pasparakis[SUP] 20 [/SUP], Stefanie Dimmeler[SUP] 2 6 [/SUP], Jindrich Cinatl[SUP] 7 [/SUP], Klaus Püschel[SUP] 21 [/SUP], Matija Zelic[SUP] 22 [/SUP], Dimitry Ofengeim[SUP] 22 [/SUP], Christine Stadelmann[SUP] 13 [/SUP], François Trottein[SUP] 10 [/SUP], Ruben Nogueiras[SUP] 23 [/SUP], Rolf Hilgenfeld[SUP] 4 5 [/SUP], Markus Glatzel[SUP] 19 [/SUP], Vincent Prevot[SUP] 12 [/SUP], Markus Schwaninger[SUP] 24 25 [/SUP]
Affiliations
- 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[SUP]pro[/SUP]) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M[SUP]pro[/SUP] 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[SUP]pro[/SUP]-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.