Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection

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Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection

Mhlekude, Baxolele (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany; Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany

Postmus, Dylan (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany

Stenzel, Saskia (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany

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Weiner, January (författare): Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany

Jansen, Jenny (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany

Zapatero-Belinchón, Francisco J. (författare): Umeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Avdelningen för virologi,Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, The Hannover Medical School, The Helmholtz Centre for Infection Research, Hannover, Germany

Olmer, Ruth (författare): Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH—Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany

Richter, Anja (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Heinze, Julian (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Heinemann, Nicolas (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Mühlemann, Barbara (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Schroeder, Simon (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Jones, Terry C. (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom

Müller, Marcel A. (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Drosten, Christian (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Pich, Andreas (författare): Institute of Toxicology, Hannover Medical School, Core Facility Proteomics, Hannover, Germany

Thiel, Volker (författare): Institute of Virology and Immunology (IVI), University of Bern, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland

Martin, Ulrich (författare): Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH—Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany

Niemeyer, Daniela (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Gerold, Gisa, 1979- (författare): Umeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Avdelningen för virologi,Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, The Hannover Medical School, The Helmholtz Centre for Infection Research, Hannover, Germany

Beule, Dieter (författare): Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany

Goffinet, Christine (författare): Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany; Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

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(creator_code:org_t)

Public Library of Science (PLoS), 2023
2023
Engelska.
Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 19:9

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://umu.diva-por... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; visa färre...

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Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19.

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Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection

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