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

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

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.