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Olagnier D , Farahani E , Thyrsted J , Blay-Cadanet J , Herengt A , Idorn M , Hait A , Hernaez B , Knudsen A , Iversen MB , Schilling M , Jørgensen SE , Thomsen M , Reinert LS , Lappe M , Hoang HD , Gilchrist VH , Hansen AL , Ottosen R , Nielsen CG , Møller C , van der Horst D , Peri S , Balachandran S , Huang J , Jakobsen M , Svenningsen EB , Poulsen TB , Bartsch L , Thielke AL , Luo Y , Alain T , Rehwinkel J , Alcamí A , Hiscott J , Mogensen TH , Paludan SR , Holm CK
SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
Nat Commun. 2020 Oct 2;11(1) :4938
PMID: 33009401    PMCID: PMC7532469   
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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.
2041-1723 Olagnier, David Orcid: 0000-0001-6912-0674 Farahani, Ensieh Thyrsted, Jacob Blay-Cadanet, Julia Herengt, Angela Idorn, Manja Orcid: 0000-0002-6769-9165 Hait, Alon Hernaez, Bruno Knudsen, Alice Iversen, Marie Beck Schilling, Mirjam Jørgensen, Sofie E Thomsen, Michelle Reinert, Line S Orcid: 0000-0002-8317-0886 Lappe, Michael Hoang, Huy-Dung Gilchrist, Victoria H Hansen, Anne Louise Ottosen, Rasmus Nielsen, Camilla G Møller, Charlotte van der Horst, Demi Peri, Suraj Balachandran, Siddharth Huang, Jinrong Jakobsen, Martin Orcid: 0000-0001-8847-9201 Svenningsen, Esben B Orcid: 0000-0001-5118-6499 Poulsen, Thomas B Bartsch, Lydia Thielke, Anne L Luo, Yonglun Orcid: 0000-0002-0007-7759 Alain, Tommy Rehwinkel, Jan Orcid: 0000-0003-3841-835x Alcamí, Antonio Orcid: 0000-0002-3333-6016 Hiscott, John Mogensen, Trine H Paludan, Søren R Orcid: 0000-0001-9180-4060 Holm, Christian K Orcid: 0000-0002-2655-3362 MRC_/Medical Research Council/United Kingdom Journal Article Research Support, Non-U.S. Gov't Nat Commun. 2020 Oct 2;11(1):4938. doi: 10.1038/s41467-020-18764-3.