Attenuation of coxsackievirus B3 by VP2 mutation and its application as a vaccine against virus-induced myocarditis and pancreatitis

Park, Jung Hyun; Kim, Dae Sun; Cho, Young Joo; Kim, Yeon Jung; Jeong, Seri; Lee, Seung Min; Cho, Seong Joo; Yun, Cheol Won; Jo, Inho; Nam, Jae Hwan

doi:10.1016/j.vaccine.2009.01.008

Cited by 29 publications

(31 citation statements)

References 41 publications

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“…Therefore, induction of potent CTLs becomes important in the development of novel preventive vaccines against viral myocarditis (55). In our study, coimmunization of chitosan-pHMGB1 with chitosan-pVP1 significantly increased virus-specific CTL responses at the mucosal site and efficiently prevented CVB3-induced myocarditis.…”

Section: Discussionmentioning

confidence: 59%

Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis

Wang

Yan

Dong

et al. 2013

Clin Vaccine Immunol

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Coxsackievirus B3 (CVB3), a small single-stranded RNA virus, belongs to the Picornaviridae family. Its infection is the most common cause of myocarditis, with no vaccine available. Gastrointestinal mucosa is the major entry port for CVB3; therefore, the induction of local immunity in mucosal tissues may help control initial viral infections and alleviate subsequent myocardial injury. Here we evaluated the ability of high-mobility group box 1 (HMGB1) encapsulated in chitosan particles to enhance the mucosal immune responses induced by the CVB3-specific mucosal DNA vaccine chitosan-pVP1. Mice were intranasally coimmunized with 4 doses of chitosan-pHMGB1 and chitosan-pVP1 plasmids, at 2-week intervals, and were challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 immunization alone, coimmunization with chitosanpHMGB1 significantly (P < 0.05) enhanced CVB3-specific fecal secretory IgA levels and promoted mucosal T cell immune responses. In accordance, reduced severity of myocarditis was observed in coimmunized mice, as evidenced by significantly (P < 0.05) reduced viral loads, decreased myocardial injury, and increased survival rates. Flow cytometric analysis indicated that HMGB1 enhanced dendritic cell (DC) recruitment to mesenteric lymph nodes and promoted DC maturation, which might partly account for its mucosal adjuvant effect. This strategy may represent a promising approach to candidate vaccines against CVB3-induced myocarditis.C oxsackieviruses belong to the Picornaviridae family with single-stranded RNA genomes and are implicated in various clinical manifestations, ranging from mild to severe life-threatening diseases (1-3). Among them, coxsackievirus B3 (CVB3) is considered to be the most common cause of viral myocarditis (4). Previous studies showed that about 5 to 50% of cases of myocarditis and its end stage of dilated cardiomyopathy, as well as congestive heart failure, are attributable to CVB3 infection (5-7). Although a few vaccine candidates have been reported to be effective in a murine CVB3-induced myocarditis model (8-10), no prophylactic or therapeutic reagent is available for the clinic to date. Thus, development of new efficient vaccines is needed urgently.Various types of CVB-specific vaccines have been examined in animal models, including inactivated or attenuated virus vaccines (11, 12), recombinant protein vaccines (13), DNA vaccines (14), and virus-like particle vaccines (8). Considering that CVB3 mainly invades hosts through the gastrointestinal tract, it is critical to induce mucosal immune responses to limit virus infection in the initial stage and at the primary site.Compared with other candidates, mucosal vaccines are more likely to induce immune tolerance rather than activation, due to their limited immunogenicity and the special mucosal environment. Therefore, discovery of safe effective mucosal adjuvants is critical to the success of mucosal vaccines. High-mobility group box 1 (HMGB1), also known as amphoterin, was originally identified as a highly ...

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Section: Discussionmentioning

confidence: 59%

Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis

Wang

Yan

Dong

et al. 2013

Clin Vaccine Immunol

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“…To test this, we constructed a recombinant CVB3 expressing FGF2 as the model protein, and showed that the recombinant virus can be used as an efficient vector for therapeutic purposes in vivo ( Figures 4 and 5). However, although CVB3 was used to make the recombinant virus, it will be necessary to use attenuated strains of CVB3, including YYFF, 28 in future research into the application of attenuated CVB3 as a safe viral vector for gene therapy.…”

Section: Discussionmentioning

confidence: 99%

“…To generate a recombinant CVB3 genome that expresses FGF2, we used an infectious cDNA of CVB3 in pBlueScript, as reported previously, 28 and the cDNA of FGF2. The CVB3 genome was modified to include an in-frame synthetic polylinker containing EcoRI and XhoI sites, into which the foreign gene could be inserted.…”

Section: Construction Of a Recombinant Infectious Viral Cdna Encodingmentioning

confidence: 99%

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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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“…The blot was incubated overnight at 4°C with a primary monoclonal anti-VP1 antibody (NCL-Entero; Novocastra Laboratories Ltd, UK) to detect viral protein expression. The membranes were washed three times and the immune complexes were detected by reactions with enhanced chemiluminescence reagents (GE Healthcare, USA), as described previously (Park et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Histone deacetylase inhibitors suppress coxsackievirus B3 growth in vitro and myocarditis induced in mice

Shim¹,

Jh²,

Mb³

et al. 2013

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Summary. -Clinical importance of myocarditis, predominantly caused by coxsackievirus B3 (CVB3), is recently rising. However, a detailed mechanism of pathogenesis of CVB3 myocarditis still needs to be clarified. Recently, it has been reported that histone modifications including acetylation are involved in coxsackievirus replication. To examine whether the CVB3 replication requires histone acetylation, histone deacetylase (HDAC) inhibitors were employed. We found that the HDAC2 activity increased in virus-infected cells at 12 hrs p.i. and that HDAC inhibitors suppressed the virus replication in vitro. This suggests that the HDAC2 activity may be required for the virus replication. Eventually, a HDAC inhibitor trichostatin A protected against CVB3-induced myocardial injury in vivo. Our results suggest that HDAC may be a novel therapeutic target for treating viral myocarditis.Keywords: coxsackievirus B3; histone acetyltransferase; histone deacetylase; HDAC inhibitors, trichostatin A; apicidin; valproic acid; shRNA; myocarditis; mouse * Corresponding author: E-mail: jhnam@catholic.ac.kr; phone: +82-2-2164-4852.

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Attenuation of coxsackievirus B3 by VP2 mutation and its application as a vaccine against virus-induced myocarditis and pancreatitis

Cited by 29 publications

References 41 publications

Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis

Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis

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

Histone deacetylase inhibitors suppress coxsackievirus B3 growth in vitro and myocarditis induced in mice

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