Inflammation of sars-cov2-infected human pluripotent stem cell-derived cardiomyocytes and the effects and side effects of remdesivir

ABSTRACT

Introduction: The global pandemic of the coronavirus 2019 disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory failures, COVID-19 patients exhibited cardiac complications. Studies observed the direct infection and replication of SARS-CoV2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) accompanied by cytopathic effects. However, the underlying mechanisms of SARS-CoV-2-mediated CM death remain poorly understood. In addition, the therapeutic potential of remdesivir (RDV) on CMs has yet to be answered. Methods and Results: We confirmed that SARS-CoV-2 is infectious to and effectively replicates in hPSC-CMs and is cytopathic to hPSC-CMs. We also found that RDV effectively inhibited viral replication at a concentration of 50 nM. RNA-seq analyses demonstrated that expression of immune responsive genes was elevated in SARS-CoV-2 infected hPSC-CMs. Immunostaining and an ELISA assay further revealed formation of inflammasomes and secretion of inflammasome-mediated cytokines, such as IL-1β, IL-18, and IL-6 in SARS-CoV-2 infected hPSC-CMs. RNA-seq analyses showed gene profile changes in SARS-CoV-2 infected hPSC-CMs corroborating with activation of inflammatory signals and cell death pathways. While gene profiles of 0.1 μM RDV-treated SARS-CoV-2-infected hPSC-CMs showed reversal of such changes, a high dose (10 μM) RDV-treated CoV-2-infected hPSC-CMs showed changes in 44% of genes expressed compared to non-RDVtreated CoV2-infected hPSC-CMs. Among those, expression of protein stability related genes, such as genes associated with autophagy and protein ubiquitination increased while expression of antiviral responsive genes decreased. In addition, a high dose of RDV inhibited expression of mitochondrial genes, particularly MitoComplex I and V compositions, which are related to energy production. Conclusions: This study demonstrates that SARS-CoV2 induced inflammasome in hPSC-CMs, which can underlie cardiac damage in addition to direct cytopathic effects. In addition, RDV can reduce inflammasome when introduced early after SARS-CoV2 infection while a high-dose can aggravate cytopathic effects by potential toxicity to mitochondria.