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

Jan Wenzel; Josephine Lampe; Helge Müller-Fielitz; 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

doi:10.1038/s41593-021-00926-1

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

Jan Wenzel, Josephine Lampe, Helge Müller-Fielitz, 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 PfefferleFlorent 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^*

^*Corresponding author for this work

206 Citations (Scopus)

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 (M^pro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M^pro 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^pro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

Original language	English
Journal	Nature Neuroscience
Volume	24
Issue number	11
Pages (from-to)	1522-1533
Number of pages	12
ISSN	1097-6256
DOIs	https://doi.org/10.1038/s41593-021-00926-1
Publication status	Published - 11.2021

Funding

We thank W. Brandt, I. Stölting, V. Hüther, A. Wohltmann, K. Schulz, R. Müller and H. Örün for expert technical help and G. Hüttmann, Lübeck, for support with STED microscopy. PLX5266 was kindly provided by Plexxikon and RIPKi was provided by Sanofi. This work was supported by grants from the European Research Council (Synergy grant no. 2019-WATCH-810331 to V.P., R.N. and M. Schwaninger), the Deutsche Forschungsgemeinschaft (SCHW 416/5-3 to M. Schwaninger; WE 6456/1-1 to J.W.; STA 1389/5-1 to C.S.; INST 392/135-1 to M. Schwaninger and P.K.; SFB 1403 (project no. 414786233) to M.P.; SFB 877 to M.G.; SFB TRR 296/1 to H.M.-F. and M. Schwaninger; SFB TRR 274 to C.S. and J.F.; and EXC 22167-390884018 to H.B.), the Marie Skłodowska-Curie European Union’s Horizon 2020 research and innovation program (no. 813294 (ENTRAIN) to J.W. and M. Schwaninger), the research consortium DEFEAT PANDEMics—National Network University Medicine funded by the Federal Ministry of Education and Research (to M.G. and C.S.), Incontinentia Pigmenti France (to M. Schwaninger), and a Roche RiSE fellowship (2017–2018; to J.L.). Work in the laboratory of R.H. was supported by the European Commission through its SCORE program (grant agreement no. 101003627). H.B., A.F. and F.O. acknowledge computational support from the OMICS compute cluster at the University of Lübeck.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 9 Industry, Innovation, and Infrastructure

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

Access to Document

10.1038/s41593-021-00926-1

Cite this

Wenzel, J., Lampe, J., Müller-Fielitz, H., Schuster, R., Zille, M., Müller, K., Krohn, M., Körbelin, J., Zhang, L., Özorhan, Ü., Neve, V., Wagner, J. U. G., Bojkova, D., Shumliakivska, M., Jiang, Y., Fähnrich, A., Ott, F., Sencio, V., Robil, C., ... Schwaninger, M. (2021). The SARS-CoV-2 main protease M^pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nature Neuroscience, 24(11), 1522-1533. https://doi.org/10.1038/s41593-021-00926-1

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

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.",

author = "Jan Wenzel and Josephine Lampe and Helge M{\"u}ller-Fielitz and Raphael Schuster and Marietta Zille and Kristin M{\"u}ller and Markus Krohn and Jakob K{\"o}rbelin and Linlin Zhang and {\"U}mit {\"O}zorhan and Vanessa Neve and Wagner, \{Julian U.G.\} and Denisa Bojkova and Mariana Shumliakivska and Yun Jiang and Anke F{\"a}hnrich and Fabian Ott and Valentin Sencio and Cyril Robil and Susanne Pfefferle and Florent Sauve and Co{\^e}lho, \{Caio Fernando Ferreira\} and Jonas Franz and Frauke Spiecker and Beate Lembrich and Sonja Binder and Nina Feller and Peter K{\"o}nig and Hauke Busch and Ludovic Collin and Roberto Villase{\~n}or and Olaf J{\"o}hren and Altmeppen, \{Hermann C.\} and Manolis Pasparakis and Stefanie Dimmeler and Jindrich Cinatl and Klaus P{\"u}schel and Matija Zelic and Dimitry Ofengeim and Christine Stadelmann and Fran{\c c}ois Trottein and Ruben Nogueiras and Rolf Hilgenfeld and Markus Glatzel and Vincent Prevot and Markus Schwaninger",

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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 2021, 'The SARS-CoV-2 main protease M^pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells', Nature Neuroscience, vol. 24, no. 11, pp. 1522-1533. https://doi.org/10.1038/s41593-021-00926-1

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T1 - The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

AU - Wenzel, Jan

AU - Lampe, Josephine

AU - Müller-Fielitz, Helge

AU - Schuster, Raphael

AU - Zille, Marietta

AU - Müller, Kristin

AU - Krohn, Markus

AU - Körbelin, Jakob

AU - Zhang, Linlin

AU - Özorhan, Ümit

AU - Neve, Vanessa

AU - Wagner, Julian U.G.

AU - Bojkova, Denisa

AU - Shumliakivska, Mariana

AU - Jiang, Yun

AU - Fähnrich, Anke

AU - Ott, Fabian

AU - Sencio, Valentin

AU - Robil, Cyril

AU - Pfefferle, Susanne

AU - Sauve, Florent

AU - Coêlho, Caio Fernando Ferreira

AU - Franz, Jonas

AU - Spiecker, Frauke

AU - Lembrich, Beate

AU - Binder, Sonja

AU - Feller, Nina

AU - König, Peter

AU - Busch, Hauke

AU - Collin, Ludovic

AU - Villaseñor, Roberto

AU - Jöhren, Olaf

AU - Altmeppen, Hermann C.

AU - Pasparakis, Manolis

AU - Dimmeler, Stefanie

AU - Cinatl, Jindrich

AU - Püschel, Klaus

AU - Zelic, Matija

AU - Ofengeim, Dimitry

AU - Stadelmann, Christine

AU - Trottein, François

AU - Nogueiras, Ruben

AU - Hilgenfeld, Rolf

AU - Glatzel, Markus

AU - Prevot, Vincent

AU - Schwaninger, Markus

PY - 2021/11

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N2 - 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.

AB - 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.

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EP - 1533

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 11

ER -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

Coronavirus related work

Access to Document

Other files and links

Fingerprint

Perfood Research Award 2021

Cite this

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

Abstract

Funding

UN SDGs

Research Areas and Centers

Coronavirus related work

Access to Document

Other files and links

Fingerprint

Prizes

Perfood Research Award 2021

Cite this

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