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

Olagnier, David; Farahani, Ensieh; Thyrsted, Jacob; Blay-Cadanet, Julia; Herengt, Angela; Idorn, Manja; Hait, Alon; Hernaez, Bruno; Knudsen, Alice; Iversen, Marie Beck; Schilling, Mirjam; Jørgensen, Sofie E.; Thomsen, Michelle; Reinert, Line S.; 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; Svenningsen, Esben B.; Poulsen, Thomas B.; Bartsch, Lydia; Thielke, Anne L.; Luo, Yonglun; Alain, Tommy; Rehwinkel, Jan; Alcamí, Antonio; Hiscott, John; Mogensen, Trine; Paludan, Søren R.; Holm, Christian K.

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.