Journal article

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

Richard J Mills, Sean J Humphrey, Patrick RJ Fortuna, Mary Lor, Simon R Foster, Gregory A Quaife-Ryan, Rebecca L Johnston, Troy Dumenil, Cameron Bishop, Rajeev Rudraraju, Daniel J Rawle, Thuy Le, Wei Zhao, Leo Lee, Charley Mackenzie-Kludas, Neda R Mehdiabadi, Christopher Halliday, Dean Gilham, Li Fu, Stephen J Nicholls Show all

CELL | CELL PRESS | Published : 2021

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 mi..

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Grants

Awarded by Medical Research Future Fund


Awarded by DFG (German Research Foundation) under Germany's Excellence Strategy


Funding Acknowledgements

We thank Clive Berghofer and Lyn Brazil (and others) for their generous philanthropic donations; Australian National Fabrication Facility Queensland Node for the fabrication of the Heart-Dyno molds; Dr. I. Anraku (QIMR Berghofer) for assistance in managing the PC3 (BSL3) facility; Dr. Alyssa Pye and Mr. Fredrick Moore (Queensland Health, Brisbane) for providing the SARS-CoV-2 virus; Grace Chojnowski and Michael Rist (QIMR Berghofer) for FACS; Tam Nguyen and Nigel Waterhouse (QIMR Berghofer) for microscopy; Nadine Shultz and Paul Collins (QIMR Berghofer) for the sequencing; Scott Wood, Pamela Mukhopadhyay, John Pearson, Nic Waddell, and Ross Koufariotis for (QIMR Berghofer) bioinformatics assistance; Ben Crossett, Angela Connolly, and Jens Altvater (University of Sydney) for mass spectrometry assistance; Compounds Australia (http://www.griffith.edu.au/science-aviation/compounds-australia) for providing access to compounds; Edouard Stanley (Murdoch Children's Research Institute) for the RM3.5 iPSC line; Translational Research Institute for Preclinical Imaging and Biological Resources Facility; and Sydney Mass Spectrometry core research facility at the University of Sydney. This work was supported by National Health and Medical Research Council of Australia (to J.E.H., M.J.S., C.R.E., T.B., and A.S.), Heart Foundation of Australia (to J.E.H.), QIMR Berghofer (to J.E.H.), The Stafford Fox Foundation (to E.R.P.), the Royal Children's Hospital Foundation (to E.R.P.), Australian Research Council Strategic Initiative in Stem Cell Science (Stem Cells Australia) (to E.R.P. and J.E.H.), and the Medical Research Future Fund (MRFF9200008 to J.E.H., T.B., M.J.S., K.P.A.M., C.R.E., and E.R.P., APP1132519 and APP1173958 to M.J.S., and APP1173880 to A.S.). Queensland Health supported this research project. The Murdoch Children's Research Institute is supported by the Victorian Government's Operational Infrastructure Support Program. T.B. is a member of ImmunoSensation2 supported by the DFG (German Research Foundation) under Germany's Excellence Strategy EXC2151 390873048. This project received support from Dynomics Snow Medical Fellowship (to J.E.H.).