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

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...

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Published inbioRxiv
Main Authors Olagnier, David, Farahani, Ensieh, Thyrsted, Jacob, Cadanet, Julia B, Herengt, Angela, Idorn, Manja, Hait, Alon, Hernaez, Bruno, Knudsen, Alice, Marie Beck Iversen, Schilling, Mirjam, Jorgensen, Sofie E, Thomsen, Michelle, Reinert, Line, Lappe, Michael, Huy-Dung Hoang, Gilchrist, Victoria H, Hansen, Anne-Louise, Ottosen, Rasmus, Gunderstofte, Camilla, Moller, Charlotte, Demi Van Der Horst, 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, Alcami, Antonio, Hiscott, John, Mogensen, Trine, Paludan, Soren R, Holm, Christian K
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 17.07.2020
Subjects
Agonists
Anti-inflammatory agents
Antiviral agents
Cell lines
Coronaviruses
COVID-19
Gene expression
Herpes simplex
Inflammation
Interferon
NRF2 protein
Oxidants
Replication
Severe acute respiratory syndrome coronavirus 2
Viruses
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Summary: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. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.07.16.206458