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BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.

ABSTRACT: SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required for ACE2 transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous ACE2 expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a novel therapeutic target for COVID-19.

SUBMITTER: Samelson AJ

PROVIDER: S-EPMC7836110 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.

Samelson Avi J AJ Tran Quang Dinh QD Robinot Rémy R Carrau Lucia L Rezelj Veronica V VV Mac Kain Alice A Chen Merissa M Ramadoss Gokul N GN Guo Xiaoyan X Lim Shion A SA Lui Irene I Nunez James J Rockwood Sarah J SJ Wang Jianhui J Liu Na N Carlson-Stevermer Jared J Oki Jennifer J Maures Travis T Holden Kevin K Weissman Jonathan S JS Wells James A JA Conklin Bruce R BR TenOever Benjamin R BR Chakrabarti Lisa A LA Vignuzzi Marco M Tian Ruilin R Kampmann Martin M

bioRxiv : the preprint server for biology 20210920

SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required for <i>ACE2</i> transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous <i>ACE2</i> expression and SARS-CoV-2 infectio ...[more]

PMID: 33501440

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Project description:The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains; previously C6orf106) was identified as a proviral factor for Hendra virus infection and was recently characterized to function as an inhibitor of type I interferon expression. Here, we have utilized transcriptome sequencing (RNA-seq) to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of Caco-2 cells. We find that inhibition of ILRUN expression by RNA interference alters transcription profiles of numerous cellular pathways, including upregulation of the SARS-CoV-2 entry receptor ACE2 and several other members of the renin-angiotensin aldosterone system. In addition, transcripts of the SARS-CoV-2 coreceptors TMPRSS2 and CTSL were also upregulated. Inhibition of ILRUN also resulted in increased SARS-CoV-2 replication, while overexpression of ILRUN had the opposite effect, identifying ILRUN as a novel antiviral factor for SARS-CoV-2 replication. This represents, to our knowledge, the first report of ILRUN as a regulator of the renin-angiotensin-aldosterone system (RAAS). IMPORTANCE There is no doubt that the current rapid global spread of COVID-19 has had significant and far-reaching impacts on our health and economy and will continue to do so. Research in emerging infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is growing rapidly, with new breakthroughs in the understanding of host-virus interactions to assist with the development of innovative and exciting therapeutic strategies. Here, we present the first evidence that modulation of the human protein-coding gene ILRUN functions as an antiviral factor for SARS-CoV-2 infection, likely through its newly identified role in regulating the expression of SARS-CoV-2 entry receptors ACE2, TMPRSS2, and CTSL. These data improve our understanding of biological pathways that regulate host factors critical to SARS-CoV-2 infection, contributing to the development of antiviral strategies to deal with the current SARS-CoV-2 pandemic.

Dataset Information

BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.

Publications

BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.

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