科研之友
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摘要
Myocarditis is indicated as the second leading cause of sudden death in young adults. Reovirus induces myocarditis in neonatal mice, providing a tractable model system for investigation of this important disease. Alpha/beta-interferon (IFN-alpha/beta) treatment improves cardiac function and inhibits viral replication in patients with chronic myocarditis, and the host IFN-alpha/beta response is a determinant of reovirus strain-specific differences in induction of myocarditis. Virus-induced IFN-beta stimulates a signaling cascade that establishes an antiviral state and further induces IFN-alpha/beta through an amplification loop. Reovirus strain-specific differences in induction of and sensitivity to IFN-alpha/beta are associated with the viral M1, L2, and S2 genes. The reovirus M1 gene-encoded mu 2 protein is a strain-specific repressor of IFN-beta signaling, providing one possible mechanism for the variation in resistance to IFN and induction of myocarditis between different reovirus strains. We report here that mu 2 amino acid 208 determines repression of IFN-beta signaling and modulates reovirus induction of IFN-beta in cardiac myocytes. Moreover, mu 2 amino acid 208 determines reovirus replication, both in initially infected cardiac myocytes and after viral spread, by regulating the IFN-beta response. Amino acid 208 of mu 2 also influences the cytopathic effect in cardiac myocytes after spread. Finally, mu 2 amino acid 208 modulates myocarditis in neonatal mice. Thus, repression of IFN-beta signaling mediated by reovirus mu 2 amino acid 208 is a determinant of the IFN-beta response, viral replication and damage in cardiac myocytes, and myocarditis. These results demonstrate that a single amino acid difference between viruses can dictate virus strain-specific differences in suppression of the host IFN-beta response and, consequently, damage to the heart.
- 出版日期2012-2
