Document Detail


A single-amino-acid polymorphism in reovirus protein μ2 determines repression of interferon signaling and modulates myocarditis.
MedLine Citation:
PMID:  22156521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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-α/β) treatment improves cardiac function and inhibits viral replication in patients with chronic myocarditis, and the host IFN-α/β response is a determinant of reovirus strain-specific differences in induction of myocarditis. Virus-induced IFN-β stimulates a signaling cascade that establishes an antiviral state and further induces IFN-α/β through an amplification loop. Reovirus strain-specific differences in induction of and sensitivity to IFN-α/β are associated with the viral M1, L2, and S2 genes. The reovirus M1 gene-encoded μ2 protein is a strain-specific repressor of IFN-β signaling, providing one possible mechanism for the variation in resistance to IFN and induction of myocarditis between different reovirus strains. We report here that μ2 amino acid 208 determines repression of IFN-β signaling and modulates reovirus induction of IFN-β in cardiac myocytes. Moreover, μ2 amino acid 208 determines reovirus replication, both in initially infected cardiac myocytes and after viral spread, by regulating the IFN-β response. Amino acid 208 of μ2 also influences the cytopathic effect in cardiac myocytes after spread. Finally, μ2 amino acid 208 modulates myocarditis in neonatal mice. Thus, repression of IFN-β signaling mediated by reovirus μ2 amino acid 208 is a determinant of the IFN-β 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-β response and, consequently, damage to the heart.
Authors:
Susan C Irvin; Jennifer Zurney; Laura S Ooms; James D Chappell; Terence S Dermody; Barbara Sherry
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2011-12-07
Journal Detail:
Title:  Journal of virology     Volume:  86     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-27     Completed Date:  2012-03-19     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2302-11     Citation Subset:  IM    
Affiliation:
Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cells, Cultured
Down-Regulation*
Humans
Interferon-alpha / genetics,  metabolism*
Interferon-beta / genetics,  metabolism*
Mammalian orthoreovirus 3 / genetics,  metabolism
Mice
Myocarditis / genetics,  metabolism*,  virology
Myocytes, Cardiac / metabolism,  virology
Orthoreovirus, Mammalian / genetics*,  metabolism
Polymorphism, Single Nucleotide*
Reoviridae Infections / genetics,  metabolism*,  virology
Signal Transduction*
Viral Proteins / genetics*
Grant Support
ID/Acronym/Agency:
CA68485/CA/NCI NIH HHS; DK20593/DK/NIDDK NIH HHS; R01 A1083333//PHS HHS; R01 AI32539/AI/NIAID NIH HHS; R37 AI38296/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Interferon-alpha; 0/Viral Proteins; 0/mu2 protein, Reovirus; 77238-31-4/Interferon-beta
Comments/Corrections

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