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

Olagnier, D.; Farahani, E.; Thyrsted, J.; Cadanet, J. B.; Herengt, A.; Idorn, M.; Hait, A.; Hernaez, B.; Knudsen, A.; Iversen, M. B.; Schilling, M.; Jorgensen, S. E.; Thomsen, M.; Reinert, L.; Lappe, M.; Hoang, H.-D.; Gilchrist, V. H.; Hansen, A.-L.; Ottosen, R.; Gunderstofte, C.; Moller, C.; van der Horst, D.; Peri, S.; Balachandran, S.; Huang, J.; Jakobsen, M.; Svenningsen, E. B.; Poulsen, T. B.; Bartsch, L.; Thielke, A. L.; Luo, Y.; Alain, T.; Rehwinkel, J.; Alcami, A.; Hiscott, J.; Mogensen, T.; Paludan, S. R.; Holm, C. K.

doi:10.1101/2020.07.16.206458

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bioRxiv · 10.1101/2020.07.16.206458

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

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Abstract

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. One Sentence SummaryNRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

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Olagnier, D., Farahani, E., Thyrsted, J., Cadanet, J. B., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudsen, A., Iversen, M. B., Schilling, M., Jorgensen, S. E., Thomsen, M., Reinert, L., Lappe, M., Hoang, H.-D., Gilchrist, V. H., Hansen, A.-L., Ottosen, R., Gunderstofte, C., Moller, C., van der Horst, D., Peri, S., Balachandran, S., Huang, J., Jakobsen, M., Svenningsen, E. B., Poulsen, T. B., Bartsch, L., Thielke, A. L., Luo, Y., Alain, T., Rehwinkel, J., Alcami, A., Hiscott, J., Mogensen, T., Paludan, S. R., Holm, C. K.. 2020-07-17. Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. https://doi.org/10.1101/2020.07.16.206458

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