TY - JOUR
T1 - The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
AU - Wenzel, Jan
AU - Lampe, Josephine
AU - Müller-Fielitz, Helge
AU - Schuster, Raphael
AU - Zille, Marietta
AU - Müller, Kristin
AU - Krohn, Markus
AU - Körbelin, Jakob
AU - Zhang, Linlin
AU - Özorhan, Ümit
AU - Neve, Vanessa
AU - Wagner, Julian U.G.
AU - Bojkova, Denisa
AU - Shumliakivska, Mariana
AU - Jiang, Yun
AU - Fähnrich, Anke
AU - Ott, Fabian
AU - Sencio, Valentin
AU - Robil, Cyril
AU - Pfefferle, Susanne
AU - Sauve, Florent
AU - Coêlho, Caio Fernando Ferreira
AU - Franz, Jonas
AU - Spiecker, Frauke
AU - Lembrich, Beate
AU - Binder, Sonja
AU - Feller, Nina
AU - König, Peter
AU - Busch, Hauke
AU - Collin, Ludovic
AU - Villaseñor, Roberto
AU - Jöhren, Olaf
AU - Altmeppen, Hermann C.
AU - Pasparakis, Manolis
AU - Dimmeler, Stefanie
AU - Cinatl, Jindrich
AU - Püschel, Klaus
AU - Zelic, Matija
AU - Ofengeim, Dimitry
AU - Stadelmann, Christine
AU - Trottein, François
AU - Nogueiras, Ruben
AU - Hilgenfeld, Rolf
AU - Glatzel, Markus
AU - Prevot, Vincent
AU - Schwaninger, Markus
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - 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 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro 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 Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
AB - 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 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro 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 Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
UR - http://www.scopus.com/inward/record.url?scp=85117445387&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/af6f19d1-e347-30bc-ac7e-f650a9c13e20/
U2 - 10.1038/s41593-021-00926-1
DO - 10.1038/s41593-021-00926-1
M3 - Journal articles
AN - SCOPUS:85117445387
VL - 24
SP - 1522
EP - 1533
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 11
ER -