Characterization of the Protective Capability of a Recombinant Coxsackievirus B3 Variant Expressing Interferon-γ

Henke, Andreas; Jarasch, Nadine; Martin, Ulrike; Zell, Roland; Wutzler, Peter

doi:10.1089/vim.2007.0077

Cited by 13 publications

(13 citation statements)

References 32 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: 55%

“…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: 55%

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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“…Some cytokines, such as murine interleukin 4 and interferon g, have been expressed from recombinant CVB3. 16 Lim et al 26 also expressed green fluorescent protein (GFP) in mouse hearts from a recombinant CVB3 variant for at least 8 weeks. The Renilla reporter protein was also transiently and extensively expressed from an attenuated recombinant CVB3 in mouse organs.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, when FGF2 was transiently expressed from CVB3 --FGF2 in mouse hindlimbs, it was functional and effective, as indicated by an improvement in blood flow and protection from ischemic necrosis in the hindlimbs injected with the recombinant CVB3 (Figures 4 and 5). Although there are obstacles to be overcome in the use of CVB3 as a gene delivery vector, such as the pathogenic risks of live virus and the effect of preexisting neutralizing antibodies directed against CVB3 on delivery efficiency, 16,17,29 CVB3 has several merits as a gene delivery vector for gene therapy. First, CVB3 does not generate a DNA intermediate that could insert into a host chromosome during replication.…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus B3 used as a gene therapy vector to express functional FGF2

Kim

et al. 2011

Gene Ther

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Current gene therapies are predominantly based on a handful of viral vectors. The limited choice of delivery vectors has been one of the stumbling blocks to the advancement of gene therapy. Therefore, the development of novel recombinant vectors should facilitate the application of gene therapies. In this study, we examined coxsackievirus B3 (CVB3) as a novel recombinant vector for the delivery and expression of a foreign gene in vitro and in vivo. A recombinant CVB3 complementary DNA was constructed by inserting a gene encoding human fibroblast growth factor 2 (FGF2). The recombinant virus (CVB3 --FGF2) efficiently expressed FGF2 in HeLa cells and human cardiomyocytes in vitro and in mouse hindlimbs in vivo. The injection of the recombinant virus into mice with ischemic hindlimbs protected the hindlimbs from ischemic necrosis. CVB3 --FGF2 injection significantly improved the blood flow in the ischemic limbs for over 3 weeks compared with that in the phosphate-buffered saline-or CVB3-injected controls, suggesting that FGF2 expressed from CVB3 --FGF2 is functional and therapeutically effective. The virulence of CVB3 was also drastically attenuated in the recombinant virus. Thus, CVB3 can be modified to express a functional foreign protein, supporting its use as a novel viral vector for gene therapy.

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