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
  • 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: [email protected].
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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