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

Autor: Baxolele Mhlekude, Dylan Postmus, Saskia Stenzel, January Weiner, Jenny Jansen, Francisco J Zapatero-Belinchón, Ruth Olmer, Anja Richter, Julian Heinze, Nicolas Heinemann, Barbara Mühlemann, Simon Schroeder, Terry C Jones, Marcel A Müller, Christian Drosten, Andreas Pich, Volker Thiel, Ulrich Martin, Daniela Niemeyer, Gisa Gerold, Dieter Beule, Christine Goffinet
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: PLoS Pathogens, Vol 19, Iss 9, p e1011657 (2023)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
67978053
DOI: 10.1371/journal.ppat.1011657&type=printable
Popis: 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.
Databáze: Directory of Open Access Journals
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