Denisa Bojkova1, Julian U G Wagner2,3, Mariana Shumliakivska2, Galip S Aslan2, Umber Saleem3,4, Arne Hansen3,4, Guillermo Luxán2, Stefan Günther5,6, Minh Duc Pham7, Jaya Krishnan6,7, Patrick N Harter8, Utz H Ermel9, Achilleas S Frangakis9, Hendrik Milting10, Andreas M Zeiher4,6,7, Karin Klingel11, Jindrich Cinatl1, Andreas Dendorfer4,12, Thomas Eschenhagen3,4, Carsten Tschöpe3,13, Sandra Ciesek1,14,15, Stefanie Dimmeler2,3,6. 1. Institute of Medical Virology, University of Frankfurt, Paul-Ehrlich-Str. 40, 60590 Frankfurt, Germany. 2. Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany. 3. German Center for Cardiovascular Research (DZHK), Germany. 4. Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 5. Max Planck Institute Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany. 6. Cardiopulmonary Institute (CPI), Frankfurt, Germany. 7. Department of Medicine, Cardiology, Goethe University Hospital, Theodor Stern Kai 7, 60590 Frankfurt, Germany. 8. Neurological Institute (Edinger Institute), University of Frankfurt, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt, Germany. 9. Institute of Biophysics and BMLS, University of Frankfurt, Campus Riedberg, Maxvon-Laue Strasse 15, 60438 Frankfurt, Germany. 10. Heart and Diabetes Center NRW, University Hospital of the Ruhr University Bochum, Clinic for Thoracic and Cardiovascular Surgery, Erich & Hanna Klessmann Institute, Georgstr. 11, 32545 Bad Oeyenhausen, Germany. 11. Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Liebermeisterstraße 8, 72076 Tuebingen, Germany. 12. Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Marchioninistr. 27, 81377 Munich, Germany. 13. Department of Cardiology, Campus Virchow Klinikum (CVK), Charité, and Berlin Institute of Health (BIH), Berlin Brandenburger Center for Regenerative Therapies (BCRT), University Medicine Berlin, Berlin, Germany. 14. Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch Translational Medicine and Pharmacology, Theodor Stern Kai 7, 60590 Frankfurt, Germany. 15. German Centre for Infection Research (DZIF), External partner site, Frankfurt, Germany.
Abstract
AIMS: Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. METHODS AND RESULTS: Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. CONCLUSION: This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. METHODS AND RESULTS: Two strains of SARS-CoV-2 infectedhuman induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. CONCLUSION: This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2infection of cardiomyocytes is inhibited by the antiviral drug remdesivir. Published on behalf of the European Society of Cardiology. All rights reserved.
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