Viral myocarditis is an important human disease associated with a wide variety of viruses. The cardiac damage and inflammation associated with viral myocarditis can be immune mediated and/or due to direct cytopathic effect. Reovirus-inducedMoreViral myocarditis is an important human disease associated with a wide variety of viruses. The cardiac damage and inflammation associated with viral myocarditis can be immune mediated and/or due to direct cytopathic effect.
Reovirus-induced myocarditis reflects direct virus-mediated apoptosis of cardiac cells, providing an excellent model to study direct cytopathic effect in the heart. Previous work has found interferon-beta (IFN-beta) to be an important determinant for protection against viral myocarditis. Importantly, IFN signals through the Jak-STAT pathway to induce the expression of interferon-stimulated genes (ISGs) and establish an antiviral state.
First, we investigated the underlying mechanisms of the IFN response in these cardiac cells. We found that high basal IFN-beta expression in cardiac myocytes protects this vulnerable, nonreplenishable cardiac cell type, while high basal expression of interferon alpha receptor 1 and latent Jak-STAT components in adjoining cardiac fibroblasts renders these cells more responsive to IFN and prevents them from inadvertently serving as a virus reservoir. This provides the first evidence for an integrated network of cell-type-specific innate immune components for organ protection.
Next, we investigated whether particular reovirus strains were able to repress IFN signaling. We found that the mildly myocarditic reovirus, T1L, but not the nonmyocarditic reovirus, T3D, could repress IFN induction of ISGs and that this repressor function is determined by the M1 gene of T1L. Infection with T1L or reassortant or recombinant viruses containing the T1L M1 gene results in accumulation of IRF9 in the nucleus- an effect not previously described for any virus.
The M1 gene has also previously been identified as a determinant of virus strain-specific differences in the IFN response, and the M1 gene and the IFN response have been identified as determinants of virus strain-specific differences in induction of murine myocarditis. Here, we find that virus-induced myocarditis is associated with repression of IFN function, providing new insights into the pathophysiology of this disease. Together, these data provide the first report of an increase in IRF9 nuclear accumulation associated with viral subversion of the IFN response, and provide evidence that virus strain-specific differences in IFN antagonism are a determinant of disease.