Journal Article

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

Møller, Charlotte, Herengt, Angela, Idorn, Manja, Holm, Christian K., Mogensen, Trine H., Huang, Jinrong, Thielke, Anne L., Hernaez, Bruno, Rehwinkel, Jan, Alain, Tommy, van der Horst, Demi, Lappe, Michael, Bartsch, Lydia, Iversen, Marie Beck, Jakobsen, Martin, Hait, Alon, Balachandran, Siddharth, Olagnier, David, Hoang, Huy-Dung, Hiscott, John, Knudsen, Alice, Poulsen, Thomas B., Jørgensen, Sofie E., Peri, Suraj, Alcamí, Antonio, Nielsen, Camilla G., Thomsen, Michelle, Blay-Cadanet, Julia, Luo, Yonglun, Farahani, Ensieh, Reinert, Line S., Gilchrist, Victoria H., Svenningsen, Esben B., Schilling, Mirjam, Thyrsted, Jacob, Ottosen, Rasmus, Hansen, Anne Louise, Paludan, Søren R.

2020

Overview

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. Viral infections usually cause disease through direct cytopathogenic effects and excessive inflammatory responses. Here, Olagnier et al. show that two NRF2 agonists, 4-OI and DMF, possess broad IFN-independent antiviral activity and decrease host inflammatory response to SARS-CoV-2 infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/109 / 13/21 / 13/31 / 13/89 / 38/109 / 38/77 / 38/91 / 631/250 / 631/326 / 631/326/596/4130 / Adult / Agonists / Anti-inflammatory agents / Anti-Inflammatory Agents - pharmacology / Antioxidants / Antioxidants - pharmacology / Antiviral activity / Antiviral Agents - pharmacology / Antiviral drugs / Betacoronavirus - drug effects / Betacoronavirus - metabolism / Cell lines / Coronavirus Infections - drug therapy / Coronavirus Infections - virology / Coronaviruses / COVID-19 / Dimethyl Fumarate - agonists / Dimethyl Fumarate - pharmacology / Female / Gene Expression / Gene Knockdown Techniques / Herpes simplex / Humanities and Social Sciences / Humans / Immunomodulators / Inflammation / Inflammatory response / Interferon / Interferon Type I / Lung - pathology / Male / multidisciplinary / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / NRF2 protein / Pandemics / Pneumonia, Viral - drug therapy / Pneumonia, Viral - virology / Replication / Respiratory diseases / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Signal Transduction - drug effects / Succinates - agonists / Succinates - pharmacology / Vector-borne diseases / Viral diseases / Viral infections / Virus Replication - drug effects / Viruses