Journal Article

The SARS-CoV-2 main protease M pro 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, Altmeppen, Hermann C, Zelic, Matija, Schuster, Raphael, Feller, Nina, Stadelmann, Christine, Spiecker, Frauke, Wagner, Julian U G, Körbelin, Jakob, Robil, Cyril, Pasparakis, Manolis, Pfefferle, Susanne, Jöhren, Olaf, Collin, Ludovic, Krohn, Markus, Hilgenfeld, Rolf, Cinatl, Jindrich, Zhang, Linlin, Shumliakivska, Mariana, Nogueiras, Ruben, 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, 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 ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M 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 -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

• Subject: Animals / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - pathology / Brain - metabolism / Brain - pathology / Chlorocebus aethiops / Coronavirus 3C Proteases - genetics / Coronavirus 3C Proteases - metabolism / Cricetinae / Female / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Male / Mesocricetus / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Microvessels - metabolism / Microvessels - pathology / SARS-CoV-2 - genetics / SARS-CoV-2 - metabolism / Vero Cells