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

  1. David Olagnier
  2. Ensieh Farahani
  3. Jacob Thyrsted
  4. Julia Blay-Cadanet
  5. Angela Herengt
  6. Manja Idorn
  7. Alon Hait
  8. Bruno Hernaez
  9. Alice Knudsen
  10. Marie Beck Iversen
  11. Mirjam Schilling
  12. Sofie E. Jørgensen
  13. Michelle Thomsen
  14. Line S. Reinert
  15. Michael Lappe
  16. Huy-Dung Hoang
  17. Victoria H. Gilchrist
  18. Anne Louise Hansen
  19. Rasmus Ottosen
  20. Camilla G. Nielsen
  21. Charlotte Møller
  22. Demi van der Horst
  23. Suraj Peri
  24. Siddharth Balachandran
  25. Jinrong Huang
  26. Martin Jakobsen
  27. Esben B. Svenningsen
  28. Thomas B. Poulsen
  29. Lydia Bartsch
  30. Anne L. Thielke
  31. Yonglun Luo
  32. Tommy Alain
  33. Jan Rehwinkel
  34. Antonio Alcamí
  35. John Hiscott
  36. Trine H. Mogensen
  37. Søren R. Paludan
  38. Christian K. Holm

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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 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.

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  1. Version published to 10.1038/s41467-020-18764-3
  2. ScreenIT

    SciScore for 10.1101/2020.07.16.206458: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2020.07.16.206458v1 on bioRxiv
  4. Version published to 10.21203/rs.3.rs-31855/v1 on Research Square