A Single-Amino-Acid Polymorphism in Reovirus Protein μ2 Determines Repression of Interferon Signaling and Modulates Myocarditis

Irvin, Susan C.; Zurney, Jennifer; Ooms, Laura S.; Chappell, James D.; Dermody, Terence S.; Sherry, Barbara

doi:10.1128/jvi.06236-11

Cited by 49 publications

(65 citation statements)

References 57 publications

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“…5E to H). and are often protective in other models of viral myocarditis (12)(13)(14). Although we did not observe virus-induced changes in IFN-␤ expression (data not shown), we did detect significant upregulation of IFN-␥ in hearts after MAV-1 infection (Fig.…”

Section: Mav-1 Infects Primary Cardiac Myocytes Ex Vivo and Hearts Inmentioning

confidence: 56%

“…CD8 ϩ T cells may play both inflammatory and cytolytic roles during infection, either by secretion of cytokines, such as IFN-␥ or TNF-␣, or through release of cytolytic granules such as Pfn (41). Both type I and type II IFN can play protective roles in other models of viral myocarditis (12)(13)(14). IFN-␥ and Pfn play antagonistic roles during chronic myocarditis caused by Trypanosoma cruzi, with Pfn ϩ CD8 ϩ T cells implicated in causing tissue damage and IFN-␥ ϩ CD8 ϩ T cells preventing tissue damage (41).…”

Section: Discussionmentioning

confidence: 99%

“…Interferon alpha (IFN-␣) and IFN-␤, the type I IFNs, are essential for limiting viral replication in cardiac myocytes and are protective in a neonatal mouse model of reovirus myocarditis (12). IFN-␥, the type II IFN, is upregulated and is often protective in models of viral myocarditis (12)(13)(14), although other reports suggest that it can promote myocarditis associated with CVB3 (15,16), and prolonged expression of IFN-␥ may lead to a chronic inflammatory cardiomyopathy (17). Myocyte apoptosis induced by viral infection and virus-in-duced inflammation can also contribute to progressive cardiac damage (18).…”

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confidence: 99%

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Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-␥) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3 ؉ T lymphocytes. Depletion of IFN-␥ during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-␥ is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction. IMPORTANCEStudying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-␥ modulation as a therapeutic strategy.

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Section: Mav-1 Infects Primary Cardiac Myocytes Ex Vivo and Hearts Inmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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“…Conservation of critical residues in the motif across reovirus serotypes suggests a role for ITAMs in viral replication and pathogenesis. Given the previously established function of 2 in modulating the IFN response and myocarditis in mice (29,35), we first focused on the ITAM sequence in 2.…”

Section: Resultsmentioning

confidence: 99%

“…Viral activation of NF-B is required for maximal induction of IFN-␤, and the IFN-␤ response is a critical determinant of protection against reovirus-induced myocarditis in mice (16,35,41). Moreover, the M1 gene (encoding the 2 protein) is the predominant determinant of reovirus induction of IFN-␤ in primary cardiac myocyte cultures (16).…”

Section: Species Proteinmentioning

confidence: 99%

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

Stebbing

Irvin

Rivera-Serrano

et al. 2014

J Virol

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: 2, 2, and 2. We demonstrate for the first time that 2 is phosphorylated, contains a functional ITAM, and activates NF-B. Specifically, 2 and NS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the 2 ITAM. Moreover, both the 2 ITAM and Syk are required for maximal 2 activation of NF-B. A mutant virus lacking the 2 ITAM activates NF-B less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-␤) than does wild-type virus despite similar replication. Notably, the consequences of these 2 ITAM effects are cell type specific. In fibroblasts where NF-B is required for reovirus-induced apoptosis, the 2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-B is not required for apoptosis, the 2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the 2 ITAM on viral spread reflects the cell type-specific effects of NF-B and IFN-␤. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host.

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The silent enemy: Celiac disease goes viral

Reale

Trevisan

Alvisi

et al. 2017

Journal Cellular Physiology

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Celiac disease is a multifactorial autoimmune chronic inflammatory disorder affecting approximately one percent of the worldwide population. In such patients, ingestion of gluten proteins from cereals like wheat, barley, and rye causes damage of the small intestine mucosa, with potentially severe consequences. Onset of the disease in predisposed individuals is believed to require a still not clearly identified external trigger, such as viral infections. A very recent study has begun to shed light on a possible mechanistic basis for this hypothesis, and surprisingly linked intestinal infections caused by common reoviruses to the onset of celiac disease.

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A Single-Amino-Acid Polymorphism in Reovirus Protein μ2 Determines Repression of Interferon Signaling and Modulates Myocarditis

Cited by 49 publications

References 57 publications

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

The silent enemy: Celiac disease goes viral

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