The cardiac interferon response to reovirus infection

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DESCRIPTION (provided by applicant): Many viruses infect the heart, and >5% of the human population has experienced some form of viral myocarditis. Unfortunately, cardiac myocytes are not replenished. This cardiac vulnerability likely necessitates a uniquely effective cardiac response, to limit virus spread through the heart until immune defenses can be deployed. Interferon-beta(IFN-beta) can provide this critical first line of defense. Viruses induce / activate interferon regulatory factors (IRFs), which induce IFN-beta expression. Secreted IFN-beta then induces a large number of interferon-stimulated genes (ISGs). Some ISGs have antiviral function and some are IRFs, which can both further induce IFN-beta and induce ISGs directly. Previously, we demonstrated that variations in cardiac damage induced by a panel of reoviruses in mice correlate with both viral induction of and sensitivity to IFN-beta in primary cardiac myocyte cultures (PCMCs). We found, however, that IFN-beta protection varied significantly between PCMCs, primary cardiac fibroblast cultures (PCFCs), and skeletal muscle cells, indicating cell type-specific differences in the IFN-beta response. Moreover, these differences were determinants of cell type-specific variations in viral replication and cytopathogenic effect. Importantly, multiple lines of evidence suggest that IRFs, IFN-beta, and ISGs function uniquely in cardiac cells. Therefore, we hypothesize that cell type-specific responses to viral infection relating to IFN-beta determine viral replication and damage in cardiac cells and the heart. In our first Aim, we will identify cell type-specific differences in expression of IFN-beta and ISGs, and determine the molecular basis for these variations. Results will identify cardiac-specific, muscle-specific, and other differences in constitutive and induced IFN-beta and ISG expression; and will identify cell type-specific variations in underlying regulatory factors. In our second Aim, we will identify cell type-specific differences in the role of IFN-beta in protection against viral replication and cell damage, and determine the molecular basis for these variations. Results will identify the role of components of the IFN-beta-response in cell type-specific differences in viral replication, cytopathogenic effect, and cardiac cell damage. In our third Aim, we will determine the role of factors that regulate IFN-beta in protection against myocarditis. In sum, results will identify cell type-specific IFN-beta-related responses critical for protection against myocarditis, potentially providing new avenues for intervention against viral infections of the heart.