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Role of the Innate Immune System in Acute Viral Myocarditis

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Abstract

Although the adaptive immune system is thought to play an important role in the pathogenesis of viral myocarditis, the role of the innate immune system has not been well defined. To address this deficiency, we employed a unique line of mice that harbor a genomic “knock in” of a mutated TNF gene lacking the AU rich element (TNFARE/ARE) that is critical for TNF mRNA stability and translation, in order to examine the contribution of the innate immune system in encephalomyocarditis-induced myocarditis (EMCV). Heterozygous mice (TNFARE/+) were infected with 500 plaque-forming units of EMCV. TNFARE/+mice had a significantly higher 14-day mortality and myocardial inflammation when compared to littermate control mice. Virologic studies showed that the viral load at 14 days was significantly lower in the hearts of TNFARE/+ mice. TNFARE/+ mice had an exaggerated proinflammatory cytokine and chemokine response in the heart following EMCV infection. Modulation of the innate immune response in TNFARE/+ mice by the late administration of prednisolone resulted in a significant improvement in survival and decreased cardiac inflammation, whereas early administration of prednisolone resulted in a blunted innate response and increased mortality in littermate control mice. Viewed together, these data suggest that the duration and degree of activation of the innate immune system plays a critical role in determining host outcomes in experimental viral myocarditis.

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Acknowledgments

The authors thank Pedro A. Piedra, MD and Alan Jewel for their invaluable help with determination of viral titers and virus neutralization studies, and Feng Gao for technical assistance. This research was supported by grants HL58081, HL42250, HL073017 (to DLM) and HL083426 (to JGV) from the National Institutes of Health.

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Authors and Affiliations

  1. Winters Center for Heart Failure Research, 1709 Dryden-BCM, 620-Rm 9.83, Houston, TX, 77030, USA

    Chien-Hua Huang, Jesus G. Vallejo & Douglas L. Mann MD

  2. Dept. of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA

    Jesus G. Vallejo

  3. Institute of Immunology, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece

    George Kollias

  4. Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, USA

    Douglas L. Mann MD

Authors
  1. Chien-Hua Huang
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  2. Jesus G. Vallejo
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  3. George Kollias
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  4. Douglas L. Mann MD
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Corresponding author

Correspondence to Douglas L. Mann MD.

Additional information

C.-H. Huang and J.G. Vallejo have equally contributed to this work.

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Huang, CH., Vallejo, J.G., Kollias, G. et al. Role of the Innate Immune System in Acute Viral Myocarditis. Basic Res Cardiol 104, 228–237 (2009). https://doi.org/10.1007/s00395-008-0765-5

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  • DOI: https://doi.org/10.1007/s00395-008-0765-5

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