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Research Article
Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
David P. Olagnier, Ensieh Farahani, Jacob Thyrsted, Julia B. Cadanet, Angela Herengt, Manja Idorn, Alon Hait, Bruno Hernaez, Alice Knudsen, Marie Beck Iversen, Mirjam Schilling, Sofie E. Jørgensen, Michelle Thomsen, Line Reinert, Michael Lappe, Huy-Dung Hoang, Victoria H. Gilchrist, Anne Louise Hansen, Rasmus Ottosen, Camilla Gunderstofte, Charlotte Møller, Jinrong Huang, Martin Jakobsen, 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
David P. Olagnier
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Corresponding Author
Ensieh Farahani
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Jacob Thyrsted
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Julia B. Cadanet
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Angela Herengt
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Manja Idorn
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Alon Hait
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Bruno Hernaez
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid), Nicolás Cabrera 1, 28049 Madrid, Spain.
Alice Knudsen
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Marie Beck Iversen
1Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Mirjam Schilling
3Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
Sofie E. Jørgensen
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Michelle Thomsen
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Line Reinert
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Michael Lappe
Omiics ApS, Åbogade 15, 8200 Aarhus N, Denmark
Huy-Dung Hoang
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L1
Victoria H. Gilchrist
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L1.
Anne Louise Hansen
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Rasmus Ottosen
Department of Chemistry, Aarhus University, Aarhus, Denmark
Camilla Gunderstofte
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Charlotte Møller
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Jinrong Huang
Lars Bolund Institute of Regenerative Medicine, BGI-Shenzhen, Shenzhen 518083, China
Martin Jakobsen
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Thomas B. Poulsen
Department of Chemistry, Aarhus University, Aarhus, Denmark
Lydia Bartsch
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany.
Anne L. Thielke
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Yonglun Luo
Lars Bolund Institute of Regenerative Medicine, BGI-Shenzhen, Shenzhen 518083, China
Tommy Alain
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L1
Jan Rehwinkel
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
Antonio Alcamí
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid), Nicolás Cabrera 1, 28049 Madrid, Spain
John Hiscott
Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161, Rome, Italy
Trine Mogensen
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Søren R. Paludan
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Christian K. Holm
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
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 anti-oxidant 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 potent cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit 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, induction of NRF2 by 4-OI and DMF limited 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 suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
One Sentence Summary: NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.
This is a preprint. It has not completed peer review.
Research Article
Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
David P. Olagnier, Ensieh Farahani, Jacob Thyrsted, Julia B. Cadanet, Angela Herengt, Manja Idorn, Alon Hait, Bruno Hernaez, Alice Knudsen, Marie Beck Iversen, Mirjam Schilling, Sofie E. Jørgensen, Michelle Thomsen, Line Reinert, Michael Lappe, Huy-Dung Hoang, Victoria H. Gilchrist, Anne Louise Hansen, Rasmus Ottosen, Camilla Gunderstofte, Charlotte Møller, Jinrong Huang, Martin Jakobsen, 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
David P. Olagnier
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Corresponding Author
Ensieh Farahani
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Jacob Thyrsted
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Julia B. Cadanet
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Angela Herengt
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Manja Idorn
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Alon Hait
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Bruno Hernaez
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid), Nicolás Cabrera 1, 28049 Madrid, Spain.
Alice Knudsen
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Marie Beck Iversen
1Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Mirjam Schilling
3Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
Sofie E. Jørgensen
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Michelle Thomsen
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Line Reinert
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Michael Lappe
Omiics ApS, Åbogade 15, 8200 Aarhus N, Denmark
Huy-Dung Hoang
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L1
Victoria H. Gilchrist
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L1.
Anne Louise Hansen
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Rasmus Ottosen
Department of Chemistry, Aarhus University, Aarhus, Denmark
Camilla Gunderstofte
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Charlotte Møller
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Jinrong Huang
Lars Bolund Institute of Regenerative Medicine, BGI-Shenzhen, Shenzhen 518083, China
Martin Jakobsen
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Thomas B. Poulsen
Department of Chemistry, Aarhus University, Aarhus, Denmark
Lydia Bartsch
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany.
Anne L. Thielke
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Yonglun Luo
Lars Bolund Institute of Regenerative Medicine, BGI-Shenzhen, Shenzhen 518083, China
Tommy Alain
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L1
Jan Rehwinkel
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
Antonio Alcamí
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid), Nicolás Cabrera 1, 28049 Madrid, Spain
John Hiscott
Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161, Rome, Italy
Trine Mogensen
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Søren R. Paludan
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
Christian K. Holm
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
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 anti-oxidant 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 potent cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit 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, induction of NRF2 by 4-OI and DMF limited 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 suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
One Sentence Summary: NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.
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Richard Hartley
commented on 10 June, 2020
Please state the sources of 4-OI and dimethyl fumarate including batch numbers if purchased.
View 1 reply
Christian Holm
replied on 10 June, 2020
We synthesised 4-OI as described here https://www.nature.com/articles/s41467-018-05861-7
DMF was from Sigma (242926)
Christian Holm
replied on 10 June, 2020
We synthesised 4-OI as described here https://www.nature.com/articles/s41467-018-05861-7 DMF was from Sigma (242926)