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The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

2021; Nature Portfolio; Volume: 24; Issue: 11 Linguagem: Inglês

10.1038/s41593-021-00926-1

1546-1726

Jan Wenzel, Josephine Lampe, Helge Müller‐Fielitz, Raphael Schuster, Marietta Zille, K.-M. Müller, Markus Krohn, Jakob Körbelin, Linlin Zhang, Ümit Özorhan, Vanessa Neve, Julian U. G. Wagner, Denisa Bojková, Mariana Shumliakivska, Yun Jiang, Anke Fähnrich, Fabian Ott, Valentin Sencio, Cyril Robil, Susanne Pfefferle, Florent Sauvé, Caio Fernando Ferreira Coêlho, Jonas Franz, Frauke Spiecker, Beate Lembrich, Sonja Binder, Nina Feller, Peter König, Hauke Busch, Ludovic Collin, Roberto Villaseñor, Olaf Jöhren, Hermann C. Altmeppen, Manolis Pasparakis, Stefanie Dimmeler, Jindřich Činátl, Klaus Püschel, Matija Zelic, Dimitry Ofengeim, Christine Stadelmann, François Trottein, Rubén Nogueiras, Rolf Hilgenfeld, Markus Glatzel, Vincent Prévot, Markus Schwaninger,

COVID-19 Clinical Research Studies

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.