The reovirus M1 gene, encoding a viral core protein, is associated with the myocarditic phenotype of a reovirus variant

Sherry, Barbara; Fields, Bernard N.

doi:10.1128/jvi.63.11.4850-4856.1989

Cited by 65 publications

(54 citation statements)

References 41 publications

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“…Association of antagonism of IFN signaling with induction of myocarditis. Previous studies using a panel of reovirus reassortants identified the reovirus M1 gene as a determinant of reovirus strain-specific differences in induction of myocarditis in mice (60). In addition, reovirus strain-specific differences in induction of and sensitivity to IFN-␣/␤ are associated with protection against myocarditis.…”

Section: T1l Represses Ifn Induction Of a Subset Of Isgsmentioning

confidence: 99%

Reovirus μ2 Protein Inhibits Interferon Signaling through a Novel Mechanism Involving Nuclear Accumulation of Interferon Regulatory Factor 9

Zurney

Kobayashi

Holm

et al. 2009

J Virol

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The secreted cytokine alpha/beta interferon (IFN-␣/␤) binds its receptor to activate the Jak-STAT signal transduction pathway, leading to formation of the heterotrimeric IFN-stimulated gene factor 3 (ISGF3) transcription complex for induction of IFN-stimulated genes (ISGs) and establishment of an antiviral state. Many viruses have evolved countermeasures to inhibit the IFN pathway, thereby subverting the innate antiviral response. Here, we demonstrate that the mildly myocarditic reovirus type 1 Lang (T1L), but not the nonmyocarditic reovirus type 3 Dearing, represses IFN induction of a subset of ISGs and that this repressor function segregates with the T1L M1 gene. Concordantly, the T1L M1 gene product, 2, dramatically inhibits IFN-␤-induced reporter gene expression. Surprisingly, T1L infection does not degrade components of the ISGF3 complex or interfere with STAT1 or STAT2 nuclear translocation as has been observed for other viruses. Instead, infection with T1L or reassortant or recombinant viruses containing the T1L M1 gene results in accumulation of interferon regulatory factor 9 (IRF9) in the nucleus. This effect has not been previously described for any virus and suggests that 2 modulates IRF9 interactions with STATs for both ISGF3 function and nuclear export. The M1 gene is a determinant of virus strain-specific differences in the IFN response, which are linked to virus strain-specific differences in induction of murine myocarditis. We find that virusinduced 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 couple virus strain-specific differences in IFN antagonism to the pathogenesis of viral myocarditis.

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Section: T1l Represses Ifn Induction Of a Subset Of Isgsmentioning

confidence: 99%

Reovirus μ2 Protein Inhibits Interferon Signaling through a Novel Mechanism Involving Nuclear Accumulation of Interferon Regulatory Factor 9

Zurney

Kobayashi

Holm

et al. 2009

J Virol

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“…Reoviruses, in contrast, are not associated with serious human disease, but provide an excellent model for study of viral pathogenesis in neonatal mice (Schiff and others 2007). Studies using reovirus reassortants have identifi ed the viral determinants of tropism and disease in the central nervous system (Weiner and others 1977) and heart (Sherry and Fields 1989;Sherry and Blum 1994), and replication in the gastrointestinal tract for spread to other animals (Keroack and Fields 1986;Bodkin and Fields 1989). The structure of the whole virion has been resolved by cryoelectron microscopy (Dryden and others 1993), and the reovirus core has been solved to 3.6 Å resolution (Reinisch and others 2000).…”

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confidence: 99%

Rotavirus and Reovirus Modulation of the Interferon Response

Sherry

2009

Journal of Interferon & Cytokine Research

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The mammalian reoviruses and rotaviruses have evolved specific mechanisms to evade the Type I interferon (IFN) antiviral response. Rotavirus likely represses the IFN response by at least 4 mechanisms. First, the rotavirus protein NSP1, most likely functioning as an E3 ligase, can induce proteasome-dependent degradation of the transcription factors IRF3, IRF5, and IRF7 to prevent their induction of IFN. Second, NSP1 can induce proteasome-dependent degradation of the ubiquitin ligase complex protein beta-TrCP, resulting in stabilization of I kappaB and concomitant failure of virus to activate NF-kappaB for induction of IFN. Third, rotavirus may sequester NF-kappaB in viroplasms. And fourth, rotavirus can prevent STAT1 and STAT2 nuclear translocation. The predominant mechanism for rotavirus inhibition of the IFN response is likely both rotavirus strain-specific and cell type-specific. The mammalian reoviruses also display strain-specific differences in their modulation of the IFN response. Reovirus activates RIG-I and IPS-1 for phosphorylation of IRF3. Reovirus-induced activation of MDA5 also participates in induction if IFN-beta, perhaps through activation of NF-kappaB. Reovirus likely inhibits the IFN response by at least 3 virus strain-specific mechanisms. First, the reovirus mu2 protein can induce an unusual nuclear accumulation of IRF9 and repress IFN-stimulated gene (ISG) expression, most likely by disrupting IRF9 function as part of the heterotrimeric transcription factor complex, ISGF3. Second, the reovirus sigma 3 protein can bind dsRNA and prevent activation of the latent antiviral effector protein PKR. And third, genetic approaches have identified the reovirus lambda 2 and sigma 2 proteins in virus strain-specific modulation of the IFN response, but the significance remains unclear. In sum, members of the family Reoviridae have evolved a variety of mechanisms to subvert the host's innate protective response.

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“…In addition to determining differences in viral yield in cultured cells, the L1 and M1 genes also play important roles in some models of reovirus pathogenesis. The L1 and M1 genes are linked to differences in the capacities of reovirus strains to produce myocarditis in immunocompetent mice (35,36), and, along with the L2 and S1 genes, L1 and M1 are associated with strain-specific differences in reovirus virulence in severe combined immunodeficiency mice (13). It is not known how viral gene products involved in RNA synthesis influence viral growth and virulence; however, it has been suggested that they alter the kinetics of viral polymerase activity in particular host tissues or exert toxic effects on the cell (1,13,36).…”

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confidence: 99%

“…The reassortants do not segregate into discrete groups based on genotype; rather, they form a continuum with ranges exceeding those of either parent. Nonetheless, the use of a large reassortant panel and sensitive statistical techniques allowed us to identify the primary genetic determinants of the observed phenotypic differences, as has been done in several previous studies (13,22,23,35,36,40,41). Based on the R 2 values obtained by linear regression, we estimate that the viral S1 and M2 genes together account for 54% of the genetically determined variance in reovirus-induced apoptosis of MDCK cells and that the viral L1 and M1 genes together account for 52% of the genetically determined variance in reovirus growth in MDCK cells.…”

mentioning

confidence: 99%

“…c Viruses are ranked from highest to lowest based on yield of infectious virus after 24 h of viral growth. experimental variability, the presence of novel mutations in some reassortant strains (36), or the effects of certain combinations of viral genes on expression of particular phenotypes (reviewed in reference 42). It is noteworthy that reassortant strains EB28 and EB97, which contain L1 and M1 genes derived from T3D yet produce high titers in MDCK cells, also grow well in cultured cardiac myocytes (23), a property that segregates with the T1L L1 and M1 genes.…”

mentioning

confidence: 99%

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Reovirus-induced apoptosis of MDCK cells is not linked to viral yield and is blocked by Bcl-2

Rodgers

Barton

Oberhaus

et al. 1997

J Virol

110

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In this study, we investigated the relationship between reovirus-induced apoptosis and viral growth. Madin-Darby canine kidney (MDCK) epithelial cells infected with prototype reovirus strains type 1 Lang (T1L) or type 3 Dearing (T3D) were found to undergo apoptosis, and T3D induced apoptosis of MDCK cells to a substantially greater extent than T1L. By using T1L ؋ T3D reassortant viruses, we found that differences in the capacities of these strains to induce apoptosis are determined by the viral S1 and M2 gene segments. These genes encode viral outer-capsid proteins that play important roles in viral entry into cells. T1L grew significantly better in MDCK cells than T3D, and these differences in growth segregated with the viral L1 and M1 gene segments. The L1 and M1 genes encode viral core proteins involved in viral RNA synthesis. Bcl-2 overexpression in MDCK cells inhibited reovirus-induced apoptosis but did not substantially affect reovirus growth. These findings indicate that differences in the capacities of reovirus strains to induce apoptosis and grow in MDCK cells are determined by different viral genes and that premature cell death by apoptosis does not limit reovirus growth in MDCK cells.

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The reovirus M1 gene, encoding a viral core protein, is associated with the myocarditic phenotype of a reovirus variant

Cited by 65 publications

References 41 publications

Reovirus μ2 Protein Inhibits Interferon Signaling through a Novel Mechanism Involving Nuclear Accumulation of Interferon Regulatory Factor 9

Reovirus μ2 Protein Inhibits Interferon Signaling through a Novel Mechanism Involving Nuclear Accumulation of Interferon Regulatory Factor 9

Rotavirus and Reovirus Modulation of the Interferon Response

Reovirus-induced apoptosis of MDCK cells is not linked to viral yield and is blocked by Bcl-2

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