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

DOI PDF Web Site 1 Citations

Abstract

<jats:title>Abstract</jats:title><jats:p>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<jats:sup>pro</jats:sup>) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M<jats:sup>pro</jats:sup> 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<jats:sup>pro</jats:sup>-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.</jats:p>

Journal

  • Nature Neuroscience

    Nature Neuroscience 24 (11), 1522-1533, 2021-10-21

    Springer Science and Business Media LLC

Citations (1)*help

See more

Report a problem

Back to top