tetano
Editor, Senior Moderator
Nat Commun
. 2020 Oct 2;11(1):4938.
doi: 10.1038/s41467-020-18764-3.
SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
David Olagnier[SUP] 1 [/SUP], Ensieh Farahani[SUP] 2 [/SUP], Jacob Thyrsted[SUP] 2 [/SUP], Julia Blay-Cadanet[SUP] 2 [/SUP], Angela Herengt[SUP] 2 [/SUP], Manja Idorn[SUP] 2 [/SUP], Alon Hait[SUP] 2 3 [/SUP], Bruno Hernaez[SUP] 4 [/SUP], Alice Knudsen[SUP] 2 [/SUP], Marie Beck Iversen[SUP] 2 [/SUP], Mirjam Schilling[SUP] 5 [/SUP], Sofie E J?rgensen[SUP] 2 3 [/SUP], Michelle Thomsen[SUP] 2 3 [/SUP], Line S Reinert[SUP] 2 [/SUP], Michael Lappe[SUP] 6 [/SUP], Huy-Dung Hoang[SUP] 7 [/SUP], Victoria H Gilchrist[SUP] 7 [/SUP], Anne Louise Hansen[SUP] 2 [/SUP], Rasmus Ottosen[SUP] 8 [/SUP], Camilla G Nielsen[SUP] 2 [/SUP], Charlotte M?ller[SUP] 2 [/SUP], Demi van der Horst[SUP] 2 [/SUP], Suraj Peri[SUP] 9 [/SUP], Siddharth Balachandran[SUP] 9 [/SUP], Jinrong Huang[SUP] 10 11 [/SUP], Martin Jakobsen[SUP] 2 [/SUP], Esben B Svenningsen[SUP] 8 [/SUP], Thomas B Poulsen[SUP] 8 [/SUP], Lydia Bartsch[SUP] 12 [/SUP], Anne L Thielke[SUP] 2 [/SUP], Yonglun Luo[SUP] 2 10 [/SUP], Tommy Alain[SUP] 7 [/SUP], Jan Rehwinkel[SUP] 5 [/SUP], Antonio Alcam?[SUP] 4 [/SUP], John Hiscott[SUP] 13 [/SUP], Trine Mogensen[SUP] 2 3 14 [/SUP], S?ren R Paludan[SUP] 2 [/SUP], Christian K Holm[SUP] 15 [/SUP]
Affiliations
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.
. 2020 Oct 2;11(1):4938.
doi: 10.1038/s41467-020-18764-3.
SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
David Olagnier[SUP] 1 [/SUP], Ensieh Farahani[SUP] 2 [/SUP], Jacob Thyrsted[SUP] 2 [/SUP], Julia Blay-Cadanet[SUP] 2 [/SUP], Angela Herengt[SUP] 2 [/SUP], Manja Idorn[SUP] 2 [/SUP], Alon Hait[SUP] 2 3 [/SUP], Bruno Hernaez[SUP] 4 [/SUP], Alice Knudsen[SUP] 2 [/SUP], Marie Beck Iversen[SUP] 2 [/SUP], Mirjam Schilling[SUP] 5 [/SUP], Sofie E J?rgensen[SUP] 2 3 [/SUP], Michelle Thomsen[SUP] 2 3 [/SUP], Line S Reinert[SUP] 2 [/SUP], Michael Lappe[SUP] 6 [/SUP], Huy-Dung Hoang[SUP] 7 [/SUP], Victoria H Gilchrist[SUP] 7 [/SUP], Anne Louise Hansen[SUP] 2 [/SUP], Rasmus Ottosen[SUP] 8 [/SUP], Camilla G Nielsen[SUP] 2 [/SUP], Charlotte M?ller[SUP] 2 [/SUP], Demi van der Horst[SUP] 2 [/SUP], Suraj Peri[SUP] 9 [/SUP], Siddharth Balachandran[SUP] 9 [/SUP], Jinrong Huang[SUP] 10 11 [/SUP], Martin Jakobsen[SUP] 2 [/SUP], Esben B Svenningsen[SUP] 8 [/SUP], Thomas B Poulsen[SUP] 8 [/SUP], Lydia Bartsch[SUP] 12 [/SUP], Anne L Thielke[SUP] 2 [/SUP], Yonglun Luo[SUP] 2 10 [/SUP], Tommy Alain[SUP] 7 [/SUP], Jan Rehwinkel[SUP] 5 [/SUP], Antonio Alcam?[SUP] 4 [/SUP], John Hiscott[SUP] 13 [/SUP], Trine Mogensen[SUP] 2 3 14 [/SUP], S?ren R Paludan[SUP] 2 [/SUP], Christian K Holm[SUP] 15 [/SUP]
Affiliations
- PMID: 33009401
- DOI: 10.1038/s41467-020-18764-3
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.