2. Academic Validation
  3. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

  • Cell. 2021 Apr 15;184(8):2167-2182.e22. doi: 10.1016/j.cell.2021.03.026.
Richard J Mills 1,  Sean J Humphrey 2,  Patrick R J Fortuna 1,  Mary Lor 1,  Simon R Foster 1,  Gregory A Quaife-Ryan 1,  Rebecca L Johnston 1,  Troy Dumenil 1,  Cameron Bishop 1,  Rajeev Rudraraju 3,  Daniel J Rawle 1,  Thuy Le 1,  Wei Zhao 4,  Leo Lee 4,  Charley Mackenzie-Kludas 4,  Neda R Mehdiabadi 5,  Christopher Halliday 6,  Dean Gilham 6,  Li Fu 6,  Stephen J Nicholls 7,  Jan Johansson 8,  Michael Sweeney 8,  Norman C W Wong 6,  Ewelina Kulikowski 6,  Kamil A Sokolowski 9,  Brian W C Tse 9,  Lynn Devilée 1,  Holly K Voges 1,  Liam T Reynolds 1,  Sophie Krumeich 1,  Ellen Mathieson 1,  Dad Abu-Bonsrah 10,  Kathy Karavendzas 5,  Brendan Griffen 11,  Drew Titmarsh 11,  David A Elliott 5,  James McMahon 12,  Andreas Suhrbier 13,  Kanta Subbarao 14,  Enzo R Porrello 15,  Mark J Smyth 1,  Christian R Engwerda 1,  Kelli P A MacDonald 1,  Tobias Bald 16,  David E James 17,  James E Hudson 18
Affiliations

Affiliations

  • 1 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
  • 2 Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia.
  • 3 The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne, Melbourne 3052, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
  • 4 The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
  • 5 Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia.
  • 6 Resverlogix Corp., Calgary T3E 6L1, AB, Canada.
  • 7 Victorian Heart Hospital, Monash University, Clayton 3168, VIC, Australia.
  • 8 Resverlogix Corp., San Francisco, CA 94104, USA.
  • 9 Preclinical Imaging Facility, Translational Research Institute, Brisbane, QLD, Australia.
  • 10 Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Paediatrics, The University of Melbourne, Melbourne 3052, VIC, Australia.
  • 11 Dynomics Inc., San Mateo, CA 94401, USA; Dynomics Pty Ltd, Brisbane 4000, QLD, Australia.
  • 12 Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne 3004, VIC, Australia; Department of Infectious Diseases, Monash Medical Centre, Clayton 3168, VIC, Australia.
  • 13 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; GVN Center of Excellence, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia.
  • 14 The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
  • 15 Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne 3052, VIC, Australia.
  • 16 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; Institute of Experimental Oncology, University Hospital Bonn, Bonn 53127, Germany.
  • 17 Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney 2006, NSW, Australia.
  • 18 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address: james.hudson@qimrberghofer.edu.au.
PMID: 33811809 DOI: 10.1016/j.cell.2021.03.026
Abstract

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac Infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA Sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 Infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Keywords

Bromodomain and extraterminal family inhibitors; COVID-19; drug discovery; heart; inflammation; organoids.

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