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

David Olagnier*, Ensieh Farahani, Jacob Thyrsted, Julia Blay-Cadanet, Angela Herengt, Manja Idorn, Alon Hait, Bruno Hernaez, Alice Knudsen, Marie Beck Iversen, Mirjam Schilling, Sofie E Jørgensen, Michelle Thomsen, Line S Reinert, Michael Lappe, Huy-Dung Hoang, Victoria H Gilchrist, Anne Louise Hansen, Rasmus Ottosen, Camilla G NielsenCharlotte Møller, Demi van der Horst, Suraj Peri, Siddharth Balachandran, Jinrong Huang, Martin Jakobsen, Esben B Svenningsen, Thomas B Poulsen, Lydia Bartsch, Anne L Thielke, Yonglun Luo, Tommy Alain, Jan Rehwinkel, Antonio Alcamí, John Hiscott, Trine H. Mogensen, Søren R Paludan, Christian K Holm*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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.

OriginalsprogEngelsk
Artikelnummer4938
TidsskriftNature Communications
Vol/bind11
Nummer1
Antal sider12
ISSN2041-1723
DOI
StatusUdgivet - okt. 2020

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