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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Published:2020-10-02
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Olagnier DavidORCID, Farahani Ensieh, Thyrsted Jacob, Blay-Cadanet Julia, Herengt Angela, Idorn ManjaORCID, Hait Alon, Hernaez Bruno, Knudsen Alice, Iversen Marie Beck, Schilling Mirjam, Jørgensen Sofie E., Thomsen Michelle, Reinert Line S.ORCID, Lappe Michael, Hoang Huy-Dung, Gilchrist Victoria H., Hansen Anne Louise, Ottosen Rasmus, Nielsen Camilla G., Møller Charlotte, van der Horst Demi, Peri Suraj, Balachandran Siddharth, Huang Jinrong, Jakobsen MartinORCID, Svenningsen Esben B.ORCID, Poulsen Thomas B., Bartsch Lydia, Thielke Anne L., Luo YonglunORCID, Alain Tommy, Rehwinkel JanORCID, Alcamí AntonioORCID, Hiscott John, Mogensen Trine H., Paludan Søren R.ORCID, Holm Christian K.ORCID
Abstract
AbstractAntiviral 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference47 articles.
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