TY - JOUR TI - SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate AU - Olagnier, David AU - Farahani, Ensieh AU - Thyrsted, Jacob AU - Blay-Cadanet, Julia AU - Herengt, Angela AU - Idorn, Manja AU - Hait, Alon AU - Hernaez, Bruno AU - Knudsen, Alice AU - Iversen, Marie Beck AU - Schilling, Mirjam AU - Jørgensen, Sofie E. AU - Thomsen, Michelle AU - Reinert, Line S. AU - Lappe, Michael AU - Hoang, Huy-Dung AU - Gilchrist, Victoria H. AU - Hansen, Anne Louise AU - Ottosen, Rasmus AU - Nielsen, Camilla G. AU - Møller, Charlotte AU - van der Horst, Demi AU - Peri, Suraj AU - Balachandran, Siddharth AU - Huang, Jinrong AU - Jakobsen, Martin AU - Svenningsen, Esben B. AU - Poulsen, Thomas B. AU - Bartsch, Lydia AU - Thielke, Anne L. AU - Luo, Yonglun AU - Alain, Tommy AU - Rehwinkel, Jan AU - Alcamí, Antonio AU - Hiscott, John AU - Mogensen, Trine AU - Paludan, Søren R. AU - Holm, Christian K. T2 - Nature Communications AB - 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. DA - 2020/10/02/ PY - 2020 DO - 10.1038/s41467-020-18764-3 DP - www.nature.com VL - 11 IS - 1 SP - 4938 LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-020-18764-3 Y2 - 2020/10/02/22:20:17 ER -