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

  • PLoS Pathog. 2023 Sep 25;19(9):e1011657. doi: 10.1371/journal.ppat.1011657.
Baxolele Mhlekude  1  2  3  4 ,  Dylan Postmus  1  2 ,  Saskia Stenzel  1  2 ,  January Weiner 3rd  2 ,  Jenny Jansen  1  2 ,  Francisco J Zapatero-Belinchón  5  6  7 ,  Ruth Olmer  8 ,  Anja Richter  1 ,  Julian Heinze  1 ,  Nicolas Heinemann  1 ,  Barbara Mühlemann  1 ,  Simon Schroeder  1 ,  Terry C Jones  1  9 ,  Marcel A Müller  1 ,  Christian Drosten  1 ,  Andreas Pich  10 ,  Volker Thiel  11  12 ,  Ulrich Martin  8 ,  Daniela Niemeyer  1 ,  Gisa Gerold  5  6  7 ,  Dieter Beule  2 ,  Christine Goffinet  1  2  13
Affiliations
  • 1. Institute of Virology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 2. Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 3. Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 4. Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany.
  • 5. Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
  • 6. Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
  • 7. Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden.
  • 8. 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.
  • 9. Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
  • 10. Institute of Toxicology, Hannover Medical School, Core Facility Proteomics, Hannover, Germany.
  • 11. Institute of Virology and Immunology (IVI), University of Bern, Bern, Switzerland.
  • 12. Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
  • 13. Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool United Kingdom.
PMID: 37747932 DOI: 10.1371/journal.ppat.1011657
Abstract

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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