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

Olagnier D., Farahani E., Thyrsted J., Blay-Cadanet J., Herengt A., Idorn M., Hait A., Hernaez B., Knudsen A., Iversen MB., Schilling M., Jørgensen SE., Thomsen M., Reinert LS., Lappe M., Hoang H-D., Gilchrist VH., Hansen AL., Ottosen R., Nielsen CG., Møller C., van der Horst D., Peri S., Balachandran S., Huang J., Jakobsen M., Svenningsen EB., Poulsen TB., Bartsch L., Thielke AL., Luo Y., Alain T., Rehwinkel J., Alcamí A., Hiscott J., Mogensen T., Paludan SR., Holm CK.

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.

DOI

10.1038/s41467-020-18764-3

Type

Journal article

Journal

Nature communications

Publication Date

02/10/2020

Volume

11

Addresses

Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark. olagnier@biomed.au.dk.

Keywords

Lung, Humans, Pneumonia, Viral, Coronavirus Infections, Succinates, Interferon Type I, Anti-Inflammatory Agents, Antioxidants, Antiviral Agents, Virus Replication, Signal Transduction, Gene Expression, Adult, Female, Male, NF-E2-Related Factor 2, Gene Knockdown Techniques, Pandemics, Dimethyl Fumarate, Betacoronavirus

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