SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

David Olagnier (), Ensieh Farahani, Jacob Thyrsted, Julia Blay-Cadanet, Angela Herengt, Manja Idorn, Alon Hait, Bruno Hernaez, Alice Knudsen, Marie Beck Iversen, Mirjam Schilling, Sofie E. Jørgensen, Michelle Thomsen, Line S. Reinert, Michael Lappe, Huy-Dung Hoang, Victoria H. Gilchrist, Anne Louise Hansen, Rasmus Ottosen, Camilla G. Nielsen, Charlotte Møller, Demi Horst, Suraj Peri, Siddharth Balachandran, Jinrong Huang, Martin Jakobsen, Esben B. Svenningsen, Thomas B. Poulsen, Lydia Bartsch, Anne L. Thielke, Yonglun Luo, Tommy Alain, Jan Rehwinkel, Antonio Alcamí, John Hiscott, Trine H. Mogensen, Søren R. Paludan and Christian K. Holm ()
Additional contact information
David Olagnier: Aarhus Research Center for Innate Immunology, Aarhus University
Ensieh Farahani: Aarhus Research Center for Innate Immunology, Aarhus University
Jacob Thyrsted: Aarhus Research Center for Innate Immunology, Aarhus University
Julia Blay-Cadanet: Aarhus Research Center for Innate Immunology, Aarhus University
Angela Herengt: Aarhus Research Center for Innate Immunology, Aarhus University
Manja Idorn: Aarhus Research Center for Innate Immunology, Aarhus University
Alon Hait: Aarhus Research Center for Innate Immunology, Aarhus University
Bruno Hernaez: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid)
Alice Knudsen: Aarhus Research Center for Innate Immunology, Aarhus University
Marie Beck Iversen: Aarhus Research Center for Innate Immunology, Aarhus University
Mirjam Schilling: University of Oxford
Sofie E. Jørgensen: Aarhus Research Center for Innate Immunology, Aarhus University
Michelle Thomsen: Aarhus Research Center for Innate Immunology, Aarhus University
Line S. Reinert: Aarhus Research Center for Innate Immunology, Aarhus University
Michael Lappe: Omiics ApS
Huy-Dung Hoang: University of Ottawa
Victoria H. Gilchrist: University of Ottawa
Anne Louise Hansen: Aarhus Research Center for Innate Immunology, Aarhus University
Rasmus Ottosen: Aarhus University
Camilla G. Nielsen: Aarhus Research Center for Innate Immunology, Aarhus University
Charlotte Møller: Aarhus Research Center for Innate Immunology, Aarhus University
Demi Horst: Aarhus Research Center for Innate Immunology, Aarhus University
Suraj Peri: Fox Chase Cancer Center
Siddharth Balachandran: Fox Chase Cancer Center
Jinrong Huang: Lars Bolund Institute of Regenerative Medicine, BGI-Shenzhen
Martin Jakobsen: Aarhus Research Center for Innate Immunology, Aarhus University
Esben B. Svenningsen: Aarhus University
Thomas B. Poulsen: Aarhus University
Lydia Bartsch: University Medical Center Göttingen
Anne L. Thielke: Aarhus Research Center for Innate Immunology, Aarhus University
Yonglun Luo: Aarhus Research Center for Innate Immunology, Aarhus University
Tommy Alain: University of Ottawa
Jan Rehwinkel: University of Oxford
Antonio Alcamí: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid)
John Hiscott: Istituto Pasteur Italia-Cenci Bolognetti Foundation
Trine H. Mogensen: Aarhus Research Center for Innate Immunology, Aarhus University
Søren R. Paludan: Aarhus Research Center for Innate Immunology, Aarhus University
Christian K. Holm: Aarhus Research Center for Innate Immunology, Aarhus University

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.

Date: 2020
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DOI: 10.1038/s41467-020-18764-3

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