Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-18764-3
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Funding
- UK Medical Research Council (MRC)
- Lundbeck foundation [R303-2018-3379, R219-2016-878, R268-2016-3927]
- Independent Research Fund Denmark - Medical Sciences [9039-00078B, 4004-00047B, 0214-00001B]
- CarlsbergFoundation
- European Research Council (ERC-AdG ENVISION) [786602]
- Marie Sklodowska-Curie Action of the European Commission [813343]
- Italian Cancer Research Society [22891]
- Novo Nordisk Fonden [NNF18OC0054782] Funding Source: researchfish
- Marie Curie Actions (MSCA) [813343] Funding Source: Marie Curie Actions (MSCA)
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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.
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