SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes
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SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. / Bojkova, Denisa; Wagner, Julian U G; Shumliakivska, Mariana; Aslan, Galip S; Saleem, Umber; Hansen, Arne; Luxán, Guillermo; Günther, Stefan; Pham, Minh Duc; Krishnan, Jaya; Harter, Patrick N; Ermel, Utz H; Frangakis, Achilleas S; Milting, Hendrik; Zeiher, Andreas M; Klingel, Karin; Cinatl, Jindrich; Dendorfer, Andreas; Eschenhagen, Thomas; Tschöpe, Carsten; Ciesek, Sandra; Dimmeler, Stefanie.
in: CARDIOVASC RES, Jahrgang 116, Nr. 14, 01.12.2020, S. 2207-2215.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes
AU - Bojkova, Denisa
AU - Wagner, Julian U G
AU - Shumliakivska, Mariana
AU - Aslan, Galip S
AU - Saleem, Umber
AU - Hansen, Arne
AU - Luxán, Guillermo
AU - Günther, Stefan
AU - Pham, Minh Duc
AU - Krishnan, Jaya
AU - Harter, Patrick N
AU - Ermel, Utz H
AU - Frangakis, Achilleas S
AU - Milting, Hendrik
AU - Zeiher, Andreas M
AU - Klingel, Karin
AU - Cinatl, Jindrich
AU - Dendorfer, Andreas
AU - Eschenhagen, Thomas
AU - Tschöpe, Carsten
AU - Ciesek, Sandra
AU - Dimmeler, Stefanie
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Adenosine Monophosphate/analogs & derivatives
KW - Alanine/analogs & derivatives
KW - Angiotensin-Converting Enzyme 2/metabolism
KW - Antiviral Agents/pharmacology
KW - Apoptosis/drug effects
KW - COVID-19/drug therapy
KW - Caco-2 Cells
KW - Cathepsins/metabolism
KW - Heart Diseases/drug therapy
KW - Host-Pathogen Interactions
KW - Humans
KW - Myocytes, Cardiac/drug effects
KW - Reactive Oxygen Species/metabolism
KW - SARS-CoV-2/drug effects
KW - Signal Transduction
U2 - 10.1093/cvr/cvaa267
DO - 10.1093/cvr/cvaa267
M3 - SCORING: Journal article
C2 - 32966582
VL - 116
SP - 2207
EP - 2215
JO - CARDIOVASC RES
JF - CARDIOVASC RES
SN - 0008-6363
IS - 14
ER -
