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Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside

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Abstract

Genetic defects of the dystrophin-glycoprotein complex (DGC) cause hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have previously described a mechanism involved in enterovirus-induced dilated cardiomyopathy: The enteroviral protease 2A directly cleaves dystrophin in the hinge 3 region, leading to functional dystrophin impairment. During infection of mice with coxsackievirus B3, the DGC in the heart is disrupted and the sarcolemmal integrity is lost in virus-infected cardiomyocytes. Additionally, dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy in vivo, suggesting a pathogenetic role of the dystrophin cleavage in enterovirus-induced cardiomyopathy. Here, we extend these experimental findings to a patient with dilated cardiomyopathy due to a coxsackievirus B2 myocarditis. Endomyocardial biopsy specimens showed an inflammatory infiltrate and myocytolysis. Immunostaining for the enteroviral capsid antigen VP1 revealed virus-infected cardiomyocytes. Focal areas of cardiomyocytes displayed a loss of the sarcolemmal staining pattern for dystrophin and β-sarcoglycan identical to previous findings in virus-infected mouse hearts. In vitro, coxsackievirus B2 protease 2A cleaved human dystrophin. These findings demonstrate that in human coxsackievirus B myocarditis a focal disruption of the DGC can principally occur and may contribute to the pathogenesis of human enterovirus-induced dilated cardiomyopathy.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (Ba1668/3-1) to C.B., NIH RO1 HL57365-01 and an AHA Established Investigator Award to K.U.K. We appreciate the assistance of Denise Herman and Neil Sawhney (Department of Medicine, University of California, San Diego) who made available the myocardial biopsy material on the patient with myocarditis, Roland Zell (Department of Virology, Schiller-University, Jena, Germany) for performing PCR of the coxsackievirus B2 protease 2A, and David Rapaport (Department of Surgery, University of California, San Diego) for help with the immunofluorescence.

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Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, California, USA

    Cornel Badorff & Kirk U. Knowlton

  2. Molecular Cardiology, Department of Medicine IV, Goethe-University, Theodor Stern-Kai 7, 60590, Frankfurt, Germany

    Cornel Badorff

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  1. Cornel Badorff
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  2. Kirk U. Knowlton
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Correspondence to Cornel Badorff.

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Badorff, C., Knowlton, K.U. Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside. Med Microbiol Immunol 193, 121–126 (2004). https://doi.org/10.1007/s00430-003-0189-7

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  • DOI: https://doi.org/10.1007/s00430-003-0189-7

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