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Pancreatic expression of interferon-γ protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis

Nature Medicine volume 6, pages 693–697 (2000)Cite this article

Abstract

Cardiovascular disease is one of the leading causes of death worldwide, and has been associated with many environmental risk factors1. Recent evidence has indicated the involvement of pathogens such as viruses as causative agents, and specifically identified the coxsackievirus B serogroup as the leading culprit2,3. Not only has coxsackievirus B3 (CB3) been identified from patients with cardiovascular disease4, but also infection of mice with CB3 strains can reproduce human clinical heart disease in rodents5,6. Several mechanisms have been proposed in an attempt to distinguish between pathology mediated by direct viral destruction of cardiac muscle cells7,8 or by the virus-induced immune response directed at infected myocytes9,10,11 or at ‘mimicked’ epitopes shared between viral and cardiac antigens12,13,14. To distinguish between these mechanisms, we infected a unique mouse that diminishes the extent of infection and spread of the virus, but allows complete immunity to the virus. Transgenic mice expressing interferon-γ in their pancreatic β cells failed to develop CB-3-induced myocarditis. This work challenges the idea of the function of the immune response and ‘molecular mimicry’ in the CB-3-induced autoimmune myocarditis model, and instead favors the idea of virus-mediated damage. These results emphasize the benefit of reducing the level of viremia early during infection, thereby reducing the incidence of virus-mediated heart damage and autoimmunity.

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Figure 1: Host survival, viral replication, transgene expression and autoantibody production after CB3 infection.
Figure 2: Histological analysis of the hearts of NOD and NOD–IFN-γ transgenic mice after infection with CB3.
Figure 3: Immunohistological analysis, for macrophages, of pancreata from NOD and NOD–IFN-γ transgenic mice.

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Acknowledgements

We thank L. Tucker, B. Yeung and L. Mocnik for screening and maintaining our mouse colony and M. Wood for his time and effort on the confocal microscope. We also thank M. Krakowski, M. Flodstrom, C. King, H. Fox and M. Buchmeier for discussions. M.S.H. has received an American Diabetes Association Career Development Award. A.L.C. was supported by a Juvenile Diabetes Foundation International Postdoctoral Fellowship. N.S. was supported by a Diabetes Interdisciplinary Research Program grant from the Juvenile Diabetes Foundation International. This is manuscript number 12676-IMM from The Scripps Research Institute.

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  1. Department of Immunology, The Scripps Research Institute 10550 N, Torrey Pines Road, La Jolla, 92037, California, USA

    Marc S. Horwitz, Antonio La Cava, Cody Fine, Enrique Rodriguez, Alex Ilic & Nora Sarvetnick

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  1. Marc S. Horwitz
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Correspondence to Nora Sarvetnick.

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Horwitz, M., La Cava, A., Fine, C. et al. Pancreatic expression of interferon-γ protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis. Nat Med 6, 693–697 (2000). https://doi.org/10.1038/76277

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