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Coxsackievirus B3-associated myocardial pathology and viral load reduced by recombinant soluble human
Bobby Yanagawa1, O Brad Spiller, Jonathan Choy
1UBC McDonald Research Laboratories/The iCAPTUR E Centre, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver British Columbia, Canada.
Insights
Decay-accelerating factor fusion protein (DAF-Fc) significantly reduced heart damage and viral load in mice infected with Coxsackievirus B3. Early DAF-Fc treatment shows promise for treating viral myocarditis and dilated cardiomyopathy.
Area of Science:
- Virology
- Immunology
- Cardiology
Background:
- Coxsackievirus B3 (CVB3) infection can cause myocarditis and dilated cardiomyopathy.
- Human decay-accelerating factor (DAF) is a CVB3 binding receptor.
- DAF-Fc is a soluble fusion protein designed to inhibit CVB3.
Purpose of the Study:
- To evaluate the in vivo efficacy of DAF-Fc against CVB3 infection.
- To determine the therapeutic potential of DAF-Fc in a mouse model of myocarditis.
Main Methods:
- Adolescent A/J mice were infected with a myopathic CVB3 strain.
- DAF-Fc treatment was administered before, during, or after infection.
- Histopathology and in situ hybridization were used to assess myocarditis and viral RNA.
- Infectious CVB3 levels in the heart were quantified.
Main Results:
- DAF-Fc treatment significantly decreased myocardial lesion area and cell death.
- Viral RNA and infectious CVB3 levels were reduced in DAF-Fc treated mice.
- Treatment preceding or concurrent with infection showed the most significant protective effects.
Conclusions:
- DAF-Fc demonstrates therapeutic potential for active myocarditis and acute dilated cardiomyopathy.
- Early administration of DAF-Fc may be crucial for efficacy.
- Further studies are needed to elucidate DAF-Fc's mechanism and optimize its use.
Abstract:
Coxsackievirus B3 (CVB3) infection can result in myocarditis, which in turn may lead to a protracted immune response and subsequent dilated cardiomyopathy. Human decay-accelerating factor (DAF), a binding receptor for CVB3, was synthesized as a soluble IgG1-Fc fusion protein (DAF-Fc). In vitro, DAF-Fc was able to inhibit complement activity and block infection by CVB3, although blockade of infection varied widely among strains of CVB3. To determine the effects of DAF-Fc in vivo, 40 adolescent A/J mice were infected with a myopathic strain of CVB3 and given DAF-Fc treatment 3 days before infection, during infection, or 3 days after infection; the mice were compared with virus alone and sham-infected animals. Sections of heart, spleen, kidney, pancreas, and liver were stained with hematoxylin and eosin and submitted to in situ hybridization for both positive-strand and negative-strand viral RNA to determine the extent of myocarditis and viral infection, respectively. Salient histopathologic features, including myocardial lesion area, cell death, calcification and inflammatory cell infiltration, pancreatitis, and hepatitis were scored without knowledge of the experimental groups. DAF-Fc treatment of mice either preceding or concurrent with CVB3 infection resulted in a significant decrease in myocardial lesion area and cell death and a reduction in the presence of viral RNA. All DAF-Fc treatment groups had reduced infectious CVB3 recoverable from the heart after infection. DAF-Fc may be a novel therapeutic agent for active myocarditis and acute dilated cardiomyopathy if given early in the infectious period, although more studies are needed to determine its mechanism and efficacy.