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

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

Abstract

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.

Bibliographical data

Original languageEnglish
ISSN1097-6256
DOIs
Publication statusPublished - 11.2021

Comment Deanary

© 2021. The Author(s).

PubMed 34675436