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

  • Nat Commun. 2020 Oct 2;11(1):4938. doi: 10.1038/s41467-020-18764-3.
David Olagnier  1 ,  Ensieh Farahani  #  2 ,  Jacob Thyrsted  #  2 ,  Julia Blay-Cadanet  #  2 ,  Angela Herengt  #  2 ,  Manja Idorn  2 ,  Alon Hait  2  3 ,  Bruno Hernaez  4 ,  Alice Knudsen  2 ,  Marie Beck Iversen  2 ,  Mirjam Schilling  5 ,  Sofie E Jørgensen  2  3 ,  Michelle Thomsen  2  3 ,  Line S Reinert  2 ,  Michael Lappe  6 ,  Huy-Dung Hoang  7 ,  Victoria H Gilchrist  7 ,  Anne Louise Hansen  2 ,  Rasmus Ottosen  8 ,  Camilla G Nielsen  2 ,  Charlotte Møller  2 ,  Demi van der Horst  2 ,  Suraj Peri  9 ,  Siddharth Balachandran  9 ,  Jinrong Huang  10  11 ,  Martin Jakobsen  2 ,  Esben B Svenningsen  8 ,  Thomas B Poulsen  8 ,  Lydia Bartsch  12 ,  Anne L Thielke  2 ,  Yonglun Luo  2  10 ,  Tommy Alain  7 ,  Jan Rehwinkel  5 ,  Antonio Alcamí  4 ,  John Hiscott  13 ,  Trine H Mogensen  2  3  14 ,  Søren R Paludan  2 ,  Christian K Holm  15
Affiliations
  • 1. Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark. [email protected].
  • 2. Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark.
  • 3. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
  • 4. Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid), Nicolás Cabrera 1, 28049, Madrid, Spain.
  • 5. Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
  • 6. Omiics ApS, Åbogade 15, 8200, Aarhus N, Denmark.
  • 7. Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, ON, K1H 8L1, Canada.
  • 8. Department of Chemistry, Aarhus University, Aarhus, Denmark.
  • 9. Fox Chase Cancer Center, 333 Cottman Avenue, Philidelphia, PA, 19111-2497, USA.
  • 10. Lars Bolund Institute of Regenerative Medicine, BGI-Shenzhen, Shenzhen, 518083, China.
  • 11. Department of Biology, University of Copenhagen, 2100, Copenhagen, Denmark.
  • 12. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • 13. Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161, Rome, Italy.
  • 14. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • 15. Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark. [email protected].
  • # Contributed equally.
PMID: 33009401 DOI: 10.1038/s41467-020-18764-3
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 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.