Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform

Arun Sharma, Caleb Marceau, Ryoko Hamaguchi, Paul W. Burridge, Kuppusamy Rajarajan, Jared M. Churko, Haodi Wu, Karim I. Sallam, Elena Matsa, Anthony C. Sturzu, Yonglu Che, Antje Ebert, Sebastian Diecke, Ping Liang, Kristy Red-Horse, Jan E. Carette, Sean M. Wu, Joseph C. Wu

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

RATIONALE:: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. However, human cardiac tissues are difficult to procure in sufficient enough quantities for studying the mechanisms of cardiac-specific viral infection. OBJECTIVE:: This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. METHODS AND RESULTS:: hiPSC-CMs were infected with a luciferase-expressing coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs for alterations in cellular morphology and calcium handling. Viral proliferation in hiPSC-CMs was quantified using bioluminescence imaging. Antiviral compounds including interferonβ1, ribavirin, pyrrolidine dithiocarbamate, and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with reported drug effects in previous studies. Mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways after interferonβ1 treatment. CONCLUSIONS:: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to predict antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that can screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion.

Original languageEnglish (US)
Pages (from-to)556-566
Number of pages11
JournalCirculation research
Volume115
Issue number6
DOIs
StatePublished - Aug 29 2014
Externally publishedYes

Keywords

  • cardiac
  • myocarditis
  • myocytes
  • stem cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Sharma, A., Marceau, C., Hamaguchi, R., Burridge, P. W., Rajarajan, K., Churko, J. M., Wu, H., Sallam, K. I., Matsa, E., Sturzu, A. C., Che, Y., Ebert, A., Diecke, S., Liang, P., Red-Horse, K., Carette, J. E., Wu, S. M., & Wu, J. C. (2014). Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform. Circulation research, 115(6), 556-566. https://doi.org/10.1161/CIRCRESAHA.115.303810