SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis

Bailey, A. L.; Dmytrenko, O.; Greenberg, L.; Bredemeyer, A. L.; Ma, P.; Liu, J.; Penna, V.; Lai, L.; Winkler, E. S.; Sviben, S.; Brooks, E.; Nair, A. P.; Heck, K. A.; Rali, A. S.; Simpson, L.; Saririan, M.; Hobohm, D.; Stump, W. T.; Fitzpatrick, J. A.; Xie, X.; Shi, P.-Y.; Hinson, J. T.; Gi, W.-T.; Schmidt, C.; Leuschner, F.; Lin, C.-Y.; Diamond, M. S.; Greenberg, M. J.; Lavine, K. J.

doi:10.1101/2020.11.04.364315

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bioRxiv · 10.1101/2020.11.04.364315

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis

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Abstract

Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.

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Bailey, A. L., Dmytrenko, O., Greenberg, L., Bredemeyer, A. L., Ma, P., Liu, J., Penna, V., Lai, L., Winkler, E. S., Sviben, S., Brooks, E., Nair, A. P., Heck, K. A., Rali, A. S., Simpson, L., Saririan, M., Hobohm, D., Stump, W. T., Fitzpatrick, J. A., Xie, X., Shi, P.-Y., Hinson, J. T., Gi, W.-T., Schmidt, C., Leuschner, F., Lin, C.-Y., Diamond, M. S., Greenberg, M. J., Lavine, K. J.. 2020-11-05. SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis. https://doi.org/10.1101/2020.11.04.364315

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