Journal Article

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

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

2021

Overview

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. A novel study led by scientists in Lübeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M pro , potentially causing cerebral COVID-19 and ‘long COVID’ symptoms.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/1 / 38/91 / 42/109 / 42/44 / 631/378/1341 / 64/110 / 64/60 / 692/699/375/1367 / 82/58 / 96/63 / Ablation / Animal Genetics and Genomics / Animal models / Apoptosis / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Blood vessels / Blood-brain barrier / Brain / Brain damage / Capillaries / Cell death / Coronaviruses / COVID-19 / Endothelial cells / Kinases / Life Sciences / Long COVID / Microvasculature / Mortality / Neurobiology / Neurosciences / Pathology / Protease / Protein kinase / Proteinase / Rarefaction / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / Signs and symptoms / Strings / Therapeutic targets / Tubes / Viral diseases