Molecular Pathogenesis of Virus-Induced Myocardial Injury

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Introduction To elucidate the mechanisms of viral myocarditis, much effort has been directed toward the immune response of the host, and relatively little has been done based on studies of the viruses themselves. Growth of a virus in a host cell is a major step in viral pathogenesis. Therefore, an understanding of viral determinants necessary for growth in heart tissue is important for elucidating the pathogenesis of viral myocarditis.Experiment 1 Two reovirus isolates (type 1 and type 3) differ in their capacity to grow in cultured mouse heart cells. The mammalian reoviruses contain a genome of 10 doublestranded RNA gene segments. By the use of 37 reassortant viruses (consisting of viruses with different combinations of genes derived from the two parents), difference in capacity of different strains to grow in heart cells was mapped to the M1 gene. The function of the M1 gene product, the mu2 protein, is largely unknown ; however, it is of particular interest that a mutation(s) in the … More M1 gene converts the virus to become myocarditic.Experiment 2 Two reovirus isolates also differ in their capacity to grow in cultured bovine aortic endothelial cells. By using 24 reassortant viruses, observed differences in the capacity of different strains to grow in cultured endothelial cells were also mapped to the M1 gene. No differences were detected in binding or proteolytic processing of viral outer capsid proteins of parental virions between the two reovirus isolates. Northern blot analysis showed a decreased production of viral mRNA in endothelial cells infected with type 3 reovirus, but not type 1. Thus, we have identified that the same M1 gene determines the growth capacity of reovirus in myocardial cells as well as endothelial cells. Humoral factors (such as TNF-alpha, interleukin 1, and IL 6) produced in virus-infected endothelial cells may participate in the pathogenesis of virus myocarditis in addition to the direct cytopathic effect of the virus in myocardial cells.Experiment 3 No reovirus genes were detected in myocardial samples (obtained by endomyocardial biopsy or autopsy) in 27 patients with myocarditis and dilated cardiomyopathy by the PCR method.Thus, reovirus in an attractive model in which to study how viruses cause myocarditis at a molecular genetic level. Less