COVID-19 can damage cerebral small vessels and cause neurological symptoms. In this article the authors 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, they found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. They 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. The authors concluded that their data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
Wenzel J, Lampe J, Müller-Fielitz H, Schuster R, Zille M, Müller K, Krohn M, Körbelin J, Zhang L, Özorhan Ü, Neve V, Wagner JUG, Bojkova D, Shumliakivska M, Jiang Y, Fähnrich A, Ott F, Sencio V, Robil C, Pfefferle S, Sauve F, Coêlho CFF, Franz J, Spiecker F, Lembrich B, Binder S, Feller N, König P, Busch H, Collin L, Villaseñor R, Jöhren O, Altmeppen HC, Pasparakis M, Dimmeler S, Cinatl J, Püschel K, Zelic M, Ofengeim D, Stadelmann C, Trottein F, Nogueiras R, Hilgenfeld R, Glatzel M, Prevot V, Schwaninger M. The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat Neurosci. 2021 Oct 21. doi: 10.1038/s41593-021-00926-1.