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| Item Type: | Article |
|---|---|
| Title: | Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection |
| Creators Name: | Mhlekude, B., Postmus, D., Stenzel, S., Weiner, J., Jansen, J., Zapatero-Belinchón, F.J., Olmer, R., Richter, A., Heinze, J., Heinemann, N., Mühlemann, B., Schroeder, S., Jones, T.C., Müller, M.A., Drosten, C., Pich, A., Thiel, V., Martin, U., Niemeyer, D., Gerold, G., Beule, D. and Goffinet, C. |
| 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. |
| Keywords: | SARS-CoV-2, Virions, Chromatin, Small Interfering RNA, Antiviral Therapy, Prophylaxis, Genomics, Coronaviruses |
| Source: | PLoS Pathogens |
| ISSN: | 1553-7366 |
| Publisher: | Public Library of Science |
| Volume: | 19 |
| Number: | 9 |
| Page Range: | e1011657 |
| Date: | 25 September 2023 |
| Official Publication: | https://doi.org/10.1371/journal.ppat.1011657 |
| PubMed: | View item in PubMed |
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