1. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
- Author
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Ester M Og Konrad Kristian Sigurdssons Dyreværnsfond, Beckett Fonden, Hørslev Fonden, Medical Research Council (UK), Lundbeck Foundation, Independent Research Fund Denmark, Carlsberg Foundation, European Research Council, European Commission, Associazione Italiana per la Ricerca sul Cancro, Olagnier, David [0000-0001-6912-0674], Idorn, Manja [0000-0002-6769-9165], Reinert, Line [0000-0002-8317-0886], Jakobsen, Martin [0000-0001-8847-9201], Svenningsen, Esben B. [0000-0001-5118-6499], Luo, Yonglun [0000-0002-0007-7759], Rehwinkel, Jan [0000-0003-3841-835X], Alcamí, Antonio [0000-0002-3333-6016], Paludan, Søren R. [0000-0001-9180-4060], Holm, Christian [0000-0002-2655-3362], Olagnier, David, Farahani, Ensieh, Thyrsted, Jacob, Blay-Cadanet, Julia, Herengt, Angela, Idorn, Manja, Hait, Alon, Hernáez, 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, Horst, Demi van der, 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, Ester M Og Konrad Kristian Sigurdssons Dyreværnsfond, Beckett Fonden, Hørslev Fonden, Medical Research Council (UK), Lundbeck Foundation, Independent Research Fund Denmark, Carlsberg Foundation, European Research Council, European Commission, Associazione Italiana per la Ricerca sul Cancro, Olagnier, David [0000-0001-6912-0674], Idorn, Manja [0000-0002-6769-9165], Reinert, Line [0000-0002-8317-0886], Jakobsen, Martin [0000-0001-8847-9201], Svenningsen, Esben B. [0000-0001-5118-6499], Luo, Yonglun [0000-0002-0007-7759], Rehwinkel, Jan [0000-0003-3841-835X], Alcamí, Antonio [0000-0002-3333-6016], Paludan, Søren R. [0000-0001-9180-4060], Holm, Christian [0000-0002-2655-3362], Olagnier, David, Farahani, Ensieh, Thyrsted, Jacob, Blay-Cadanet, Julia, Herengt, Angela, Idorn, Manja, Hait, Alon, Hernáez, 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, Horst, Demi van der, 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., and Holm, Christian
- 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.
- Published
- 2020