SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes-Reference-Cited by-同舟云学术

SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

Published:2020-09-23 Issue:14 Volume:116 Page:2207-2215
ISSN:0008-6363
Container-title:Cardiovascular Research
language:en
Short-container-title:

Author:

Bojkova Denisa¹,Wagner Julian U G²³,Shumliakivska Mariana²^ORCID,Aslan Galip S²^ORCID,Saleem Umber³⁴,Hansen Arne³⁴,Luxán Guillermo²^ORCID,Günther Stefan⁵⁶^ORCID,Pham Minh Duc⁷^ORCID,Krishnan Jaya⁶⁷^ORCID,Harter Patrick N⁸,Ermel Utz H⁹^ORCID,Frangakis Achilleas S⁹,Milting Hendrik¹⁰,Zeiher Andreas M⁴⁶⁷^ORCID,Klingel Karin¹¹^ORCID,Cinatl Jindrich¹,Dendorfer Andreas⁴¹²,Eschenhagen Thomas³⁴^ORCID,Tschöpe Carsten³¹³,Ciesek Sandra¹¹⁴¹⁵,Dimmeler Stefanie²³⁶^ORCID

Affiliation:

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

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.

Funder

German Center for Cardiovascular Research

DZHK

Excellence Strategy Program

German Heart Foundation

Pfizer Foundation

European Innovation Council

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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