REOVIRUS INDUCTION OF AND SENSITIVITY TO BETA-INTERFERON IN CARDIAC MYOCYTE CULTURES CORRELATE WITH INDUCTION OF MYOCARDITIS AND ARE DETERMINED BY VIRAL CORE PROTEINS

Reovirus-induced acute myocarditis in mice serves as a model to invest igate nan immune-mediated mechanisms of viral myocarditis. We have use d primary cardiac myocyte cultures infected with a large panel of myoc arditic and nonmyocarditic reassortant reoviruses to identify determin ants of viral myocarditic potential, Here, we report that while both m yocarditic and nonmyocarditic reoviruses kill cardiac myocytes, viral myocarditic potential correlates with viral spread through cardiac myo cyte cultures and with cumulative cell death, To address the role of s ecreted interferon (IFN), we added anti-IFN-alpha/beta antibody to inf ected cardiac myocyte cultures, Antibody benefited nonmyocarditic more than myocarditic virus spread (P < 0.001), and this benefit was assoc iated with the reovirus M1 and L2 genes, There was no benefit for a di fferentiated skeletal muscle fell line culture (C2C12 cells), suggesti ng cell type specificity. IFN-beta induction in reovirus-infected card iac myocyte cultures correlated with viral myocarditic potential (P = 0.006) and was associated with the reovirus M1, S2 and L2 genes, Sensi tivity to the antiviral effects of IFN-alpha/beta added to cardiac myo cyte cultures also correlated with viral myocarditic potential (P = 0. 004) and was associated with the same reovirus genes, Several reovirus es induced IFN-beta levels discordant with their myocarditic phenotype s, and for those tested, sensitivity to IFN-alpha/beta compensated for the anomalous induction levels. Thus, the combination of induction of and sensitivity to IFN-alpha/beta is a determinant of reovirus myocar ditic potential, Finally, a nonmyocarditic reovirus induced cardiac le sions in mice depleted of IFN-alpha/beta, demonstrating that IFN-alpha /beta is a determinant of reovirus-induced myocarditis. This provides the first identification of reovirus genes associated with IFN inducti on and sensitivity and provides the first evidence that IFN-beta can b e a determinant of viral myocarditis and reovirus disease.