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. Nielsen; Charlotte 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 Mogensen; Søren R. Paludan; Christian K. Holm

doi:10.1038/s41467-020-18764-3

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 Mogensen, Søren R. Paludan, Christian K. Holm

Research output: Contribution to journal › Article › peer-review

292 Scopus citations

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.

Original language	English
Article number	4938
Pages (from-to)	4938
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18764-3
State	Published - Sep 2 2020

Keywords

Adult
Anti-Inflammatory Agents/pharmacology
Antioxidants/pharmacology
Antiviral Agents/pharmacology
Betacoronavirus/drug effects
COVID-19
Coronavirus Infections/drug therapy
Dimethyl Fumarate/agonists
Female
Gene Expression
Gene Knockdown Techniques
Humans
Interferon Type I
Lung/pathology
Male
NF-E2-Related Factor 2/genetics
Pandemics
Pneumonia, Viral/drug therapy
SARS-CoV-2
Signal Transduction/drug effects
Succinates/agonists
Virus Replication/drug effects

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-020-18764-3

Cite this

Olagnier, D., Farahani, E., Thyrsted, J., Blay-Cadanet, J., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudsen, A., Iversen, M. B., Schilling, M., Jørgensen, S. E., Thomsen, M., Reinert, L. S., Lappe, M., Hoang, H. D., Gilchrist, V. H., Hansen, A. L., Ottosen, R., ... Holm, C. K. (2020). SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nature Communications, 11(1), 4938. Article 4938. https://doi.org/10.1038/s41467-020-18764-3

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

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.",

keywords = "Adult, Anti-Inflammatory Agents/pharmacology, Antioxidants/pharmacology, Antiviral Agents/pharmacology, Betacoronavirus/drug effects, COVID-19, Coronavirus Infections/drug therapy, Dimethyl Fumarate/agonists, Female, Gene Expression, Gene Knockdown Techniques, Humans, Interferon Type I, Lung/pathology, Male, NF-E2-Related Factor 2/genetics, Pandemics, Pneumonia, Viral/drug therapy, SARS-CoV-2, Signal Transduction/drug effects, Succinates/agonists, Virus Replication/drug effects",

author = "David Olagnier and Ensieh Farahani and Jacob Thyrsted and Julia Blay-Cadanet and Angela Herengt and Manja Idorn and Alon Hait and Bruno Hernaez and Alice Knudsen and Iversen, {Marie Beck} and Mirjam Schilling and J{\o}rgensen, {Sofie E.} and Michelle Thomsen and Reinert, {Line S.} and Michael Lappe and Hoang, {Huy Dung} and Gilchrist, {Victoria H.} and Hansen, {Anne Louise} and Rasmus Ottosen and Nielsen, {Camilla G.} and Charlotte M{\o}ller and {van der Horst}, Demi and Suraj Peri and Siddharth Balachandran and Jinrong Huang and Martin Jakobsen and Svenningsen, {Esben B.} and Poulsen, {Thomas B.} and Lydia Bartsch and Thielke, {Anne L.} and Yonglun Luo and Tommy Alain and Jan Rehwinkel and Antonio Alcam{\'i} and John Hiscott and Trine Mogensen and Paludan, {S{\o}ren R.} and Holm, {Christian K.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = sep,

day = "2",

doi = "10.1038/s41467-020-18764-3",

language = "English",

volume = "11",

pages = "4938",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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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, HD, 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 2020, 'SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate', Nature Communications, vol. 11, no. 1, 4938, pp. 4938. https://doi.org/10.1038/s41467-020-18764-3

TY - JOUR

T1 - SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

AU - Olagnier, David

AU - Farahani, Ensieh

AU - Thyrsted, Jacob

AU - Blay-Cadanet, Julia

AU - Herengt, Angela

AU - Idorn, Manja

AU - Hait, Alon

AU - Hernaez, Bruno

AU - Knudsen, Alice

AU - Iversen, Marie Beck

AU - Schilling, Mirjam

AU - Jørgensen, Sofie E.

AU - Thomsen, Michelle

AU - Reinert, Line S.

AU - Lappe, Michael

AU - Hoang, Huy Dung

AU - Gilchrist, Victoria H.

AU - Hansen, Anne Louise

AU - Ottosen, Rasmus

AU - Nielsen, Camilla G.

AU - Møller, Charlotte

AU - van der Horst, Demi

AU - Peri, Suraj

AU - Balachandran, Siddharth

AU - Huang, Jinrong

AU - Jakobsen, Martin

AU - Svenningsen, Esben B.

AU - Poulsen, Thomas B.

AU - Bartsch, Lydia

AU - Thielke, Anne L.

AU - Luo, Yonglun

AU - Alain, Tommy

AU - Rehwinkel, Jan

AU - Alcamí, Antonio

AU - Hiscott, John

AU - Mogensen, Trine

AU - Paludan, Søren R.

AU - Holm, Christian K.

PY - 2020/9/2

Y1 - 2020/9/2

N2 - 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.

AB - 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.

KW - Adult

KW - Anti-Inflammatory Agents/pharmacology

KW - Antioxidants/pharmacology

KW - Antiviral Agents/pharmacology

KW - Betacoronavirus/drug effects

KW - COVID-19

KW - Coronavirus Infections/drug therapy

KW - Dimethyl Fumarate/agonists

KW - Female

KW - Gene Expression

KW - Gene Knockdown Techniques

KW - Humans

KW - Interferon Type I

KW - Lung/pathology

KW - Male

KW - NF-E2-Related Factor 2/genetics

KW - Pandemics

KW - Pneumonia, Viral/drug therapy

KW - SARS-CoV-2

KW - Signal Transduction/drug effects

KW - Succinates/agonists

KW - Virus Replication/drug effects

UR - http://www.scopus.com/inward/record.url?scp=85091870221&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-18764-3

DO - 10.1038/s41467-020-18764-3

M3 - Article

C2 - 33009401

AN - SCOPUS:85091870221

SN - 2041-1723

VL - 11

SP - 4938

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4938

ER -

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

Abstract

Keywords

UN SDGs

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

Abstract

Keywords

UN SDGs

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