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

Olagnier, David; Farahani, Ensieh; Thyrsted, Jacob; Cadanet, Julia B.; Herengt, Angela; Idorn, Manja; Hait, Alon; Hernaez, Bruno; Knudsen, Alice; Iversen, Marie Beck; Schilling, Mirjam; Jørgensen, Sofie E.; Thomsen, Michelle; Reinert, Line; Lappe, Michael; Hoang, Huy-Dung; Gilchrist, Victoria H.; Hansen, Anne Louise; Ottosen, Rasmus; Gunderstofte, Camilla; Møller, Charlotte; van der Horst, Demi; Peri, Suraj; Balachandran, Siddarth; 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 anti-oxidant 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 anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit 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, induction of NRF2 by 4-OI and DMF limited 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 suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence Summary NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.