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

Jan Wenzel, Josephine Lampe, Helge Müller-Fielitz, Raphael Schuster, Marietta Zille, Kristin Müller, Markus Krohn, Jakob Körbelin, Linlin Zhang, Ümit Özorhan, Vanessa Neve, Julian U.G. Wagner, Denisa Bojkova, Mariana Shumliakivska, Yun Jiang, Anke Fähnrich, Fabian Ott, Valentin Sencio, Cyril Robil, Susanne PfefferleFlorent Sauve, 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, Jindrich Cinatl, Klaus Püschel, Matija Zelic, Dimitry Ofengeim, Christine Stadelmann, François Trottein, Ruben Nogueiras, Rolf Hilgenfeld, Markus Glatzel, Vincent Prevot, Markus Schwaninger*

*Corresponding author for this work


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.

Original languageEnglish
JournalNature Neuroscience
Issue number11
Pages (from-to)1522-1533
Number of pages12
Publication statusPublished - 11.2021

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19


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