Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis.
Cardiovascular disease is one of the leading causes of death worldwide, and has been associated with many environmental risk factors. Recent evidence has indicated the involvement of pathogens such as viruses as causative agents, and specifically identified the coxsackievirus B serogroup as the leading culprit. Not only has coxsackievirus B3 (CB3) been identified from patients with cardiovascular disease, but also infection of mice with CB3 strains can reproduce human clinical heart disease in rodents. Several mechanisms have been proposed in an attempt to distinguish between pathology mediated by direct viral destruction of cardiac muscle cells or by the virus-induced immune response directed at infected myocytes or at 'mimicked' epitopes shared between viral and cardiac antigens. 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-gamma in their pancreatic beta 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.
Horwitz
M S
MS
Department of Immunology, The Scripps Research Institute 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
La Cava
A
A
Fine
C
C
Rodriguez
E
E
Ilic
A
A
Sarvetnick
N
N
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000276:immunology*; D015870:Gene Expression; D006367:HeLa Cells; D006321:Heart / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000276:immunology; D010179:Pancreas / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D007371:Interferon-gamma; D009218:Myosins