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

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

In: Nature Communications, Vol. 11, No. 1, 4938, 10.2020.

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@article{3186bbcd508f49c4981dbb873ec17e05,
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.",
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 Huy-Dung Hoang 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 Mogensen, {Trine H.} and Paludan, {S{\o}ren R} and Holm, {Christian K}",
year = "2020",
month = oct,
doi = "10.1038/s41467-020-18764-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

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 H.

AU - Paludan, Søren R

AU - Holm, Christian K

PY - 2020/10

Y1 - 2020/10

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.

U2 - 10.1038/s41467-020-18764-3

DO - 10.1038/s41467-020-18764-3

M3 - Journal article

C2 - 33009401

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4938

ER -