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

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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 ¹ , Ensieh Farahani ² , Jacob Thyrsted ² , Julia Blay-Cadanet ² , Angela Herengt ² , Manja Idorn ² , Alon Hait ^{2 3} , Bruno Hernaez ⁴ , Alice Knudsen ² , Marie Beck Iversen ² , Mirjam Schilling ⁵ , Sofie E J?rgensen ^{2 3} , Michelle Thomsen ^{2 3} , Line S Reinert ² , Michael Lappe ⁶ , Huy-Dung Hoang ⁷ , Victoria H Gilchrist ⁷ , Anne Louise Hansen ² , Rasmus Ottosen ⁸ , Camilla G Nielsen ² , Charlotte M?ller ² , Demi van der Horst ² , Suraj Peri ⁹ , Siddharth Balachandran ⁹ , Jinrong Huang ^{10 11} , Martin Jakobsen ² , Esben B Svenningsen ⁸ , Thomas B Poulsen ⁸ , Lydia Bartsch ¹² , Anne L Thielke ² , Yonglun Luo ^{2 10} , Tommy Alain ⁷ , Jan Rehwinkel ⁵ , Antonio Alcam? ⁴ , John Hiscott ¹³ , Trine Mogensen ^{2 3 14} , S?ren R Paludan ² , Christian K Holm ¹⁵



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.