Complete genome sequence of a human coxsackievirus b3 from a child with myocarditis in beijing, china.
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ABSTRACT:
SUBMITTER: Du J
PROVIDER: S-EPMC3569342 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
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Complete genome sequence of a human coxsackievirus b3 from a child with myocarditis in beijing, china.
Du Jiang J Wu Zhiqiang Z Xue Ying Y Zhang Ting T Yang Fan F Jin Qi Q
Genome announcements 20130101 1
A human coxsackievirus B3 (CVB3), designated strain Beijing0811, was isolated from a child diagnosed with hospital-acquired infectious acute myocarditis in Beijing, China, and propagated in human rhabdomyosarcoma cells. The complete genome sequence of this virus was 7,402 nucleotides, excluding the 3' poly(A) tail, which encoded a large polyprotein with 2,185 amino acids. This report will help us to analyze the evolutionary and epidemic characteristics of CVB3. ...[more]
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Project description:Recombination events were found in two human coxsackievirus B3 strains, Beijing0811 and SD2012CHN. The strains were isolated separately from five newborns diagnosed with severe hospital-acquired acute myocarditis in Beijing in 2008 and from two children diagnosed with hand, foot, and mouth disease with concurrent acute myocarditis in Shandong in 2012.
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Project description:Studies on inflammatory disorders elucidated the pivotal role of the CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with severe cardiac inflammation, which may progress to heart failure. We therefore investigated the influence of CX3CR1 ablation in the model of acute myocarditis, which was induced by inoculation with 5x105 plaque forming units of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days after infection, myocardial inflammation, remodeling, and titin expression and phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q diamond stain. Cardiac function was assessed by tip catheter. Compared to WT CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression of inflammatory cytokines and chemokines, which was associated with an increase of immune cell infiltration/presence. This shift towards a pro-inflammatory immune response further resulted in increased cardiac fibrosis and cardiomyocyte apoptosis, which was reflected by an impaired cardiac function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings demonstrate a cardioprotective role of CX3CR1 in CVB3-infected mice and indicate the relevance of the CX3CL1/CX3CR1 system in CVB3-induced myocarditis.
| S-EPMC5553786 | biostudies-literature
Project description:BackgroundIn recent years, the reported infection cases by coxsackievirus (CV) have been on the rise. In order to reveal the relationship between the nucleotide and amino acid sequences and the viral virulence of the CVB3/MKP strain causing myocarditis, we initially confirmed the virulence of the strain in myocardial tissue and then carried out the whole genome sequencing of CVB3/MKP strain and performed a phylogenetic analysis among different CVB3 strains.MethodsCVB3/MKP infected mouse model was established to check lesions of myocardial tissue in mice using immunohistochemical detection at different periods. RT-PCR analysis was used to amplify seven fragments covering the whole viral sequence and comparable analysis was performed.ResultsThe immunohistochemical results showed that particles of CVB3/MKP virus persisted in the cardiac tissue and caused severe pathology. The length of whole genome sequence of CVB3/MKP strain was 7400 bp. CVB3/MKP had 99.7% and 99.6% homology in nucleotide sequence with CVB3/28 and non-virulent CVB3/0, respectively. The former can induce pancreatitis and myocarditis. The nucleotide sequence in the 5'untranslated region of CVB3/MKP strain shared 99.6% and 99.5% homology with CVB3/20 and CVB3/Nancy, respectively.ConclusionWe confirmed in our animal experiments that CVB3/MKP had cardiotoxicity. CVB3/MKP, CVB3/28, and CVB3/0 may share evolutionary convergence and the 5'untranslated region (5'UTR) may be associated with virulence phenotype. Our findings will provide a basis for identifying the genomic determinant of viral virulence of CVB3/MKP strain and phylogenetic relationship among different CVB3 strains.
| S-EPMC3996064 | biostudies-literature
Project description:Coxsackievirus B3 (CVB3) is an enterovirus in the family Picornaviridae that is significant to human health, being associated with myocarditis, aseptic meningitis, and pancreatitis, among other conditions. In addition to humans, Sichuan snub-nosed monkeys can be infected and killed by CVB3. Here, we report the first complete genome sequence of a novel coxsackievirus B3 strain, SSM-CVB3, which was isolated from a deceased Sichuan snub-nosed monkey with severe myocarditis. Our findings may aid in understanding the evolutionary characteristics and molecular pathogenesis of this virus.
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Project description:BACKGROUND: Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-?. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-? mRNA expression. CONCLUSIONS: We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis.
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Project description:AimsCoxsackievirus B3 (CVB3) is known to be an important cause of myocarditis and dilated cardiomyopathy. Enterovirus-2C (E2C) is a viral RNA helicase. It inhibits host protein synthesis. Based on these facts, we hypothesize that the inhibition of 2C may suppress virus replication and prevent enterovirus-mediated cardiomyopathy.Methods and resultsWe generated a chemically modified enterovirus-2C inhibitor (E2CI). From the in vitro assay, E2CI was showed strong antiviral effects. For in vivo testing, mice were treated with E2CI intraperitoneally injected daily for three consecutive days at a dose of 8mg/kg per day, after CVB3 post-infection (p.i) (CVB3 + E2CI, n = 33). For the infected controls (CVB3 only, n = 35), mice were injected with PBS (phosphate buffered saline) in a DBA/2 strain to establish chronic myocarditis. The four-week survival rate of E2CI-treated mice was significantly higher than that of controls (92% vs. 71%; p < 0.05). Virus titers and myocardial damage were significantly reduced in the E2CI treated group. In addition, echocardiography indicated that E2CI administration dramatically maintained mouse heart function compared to control at day 28 p.i chronic stage (LVIDD, 3.1 ± 0.08 vs. 3.9 ± 0.09, p < 0.01; LVDS, 2.0 ± 0.07 vs. 2.5 ± 0.07, p < 0.001; FS, 34.8 ± 1.6% vs. 28.5 ± 1.5%; EF, 67. 9 ± 2.9% vs. 54.7 ± 4.7%, p < 0.05; CVB3 + E2CI, n = 6 vs. CVB3, n = 4). Moreover, E2CI is effectively worked in human iPS (induced pluripotent stem cell) derived cardiomyocytes.ConclusionEnterovirus-2C inhibitor (E2CI) was significantly reduced viral replication, chronic myocardium damage, and CVB3-induced mortality in DBA/2 mice. These results suggested that E2CI is a novel therapeutic agent for the treatment of enterovirus-mediated diseases.
| S-EPMC7246926 | biostudies-literature
Project description:AIMS: Coxsackievirus B3 (CVB3)-induced myocarditis, initially considered a sole immune-mediated disease, also results from a direct CVB3-mediated injury of the cardiomyocytes. Mesenchymal stem cells (MSCs) have, besides immunomodulatory, also anti-apoptotic features. In view of clinical translation, we first analysed whether MSCs can be infected by CVB3. Next, we explored whether and how MSCs could reduce the direct CVB3-mediated cardiomyocyte injury and viral progeny release, in vitro, in the absence of immune cells. Finally, we investigated whether MSC application could improve murine acute CVB3-induced myocarditis. METHODS AND RESULTS: Phase contrast pictures and MTS viability assay demonstrated that MSCs did not suffer from CVB3 infection 4-12-24-48 h after CVB3 infection. Coxsackievirus B3 RNA copy number decreased in this time frame, suggesting that no CVB3 replication took place. Co-culture of MSCs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis, oxidative stress, intracellular viral particle production, and viral progeny release in a nitric oxide (NO)-dependent manner. Moreover, MSCs required priming via interferon-? (IFN-?) to exert their protective effects. In vivo, MSC application improved the contractility and relaxation parameters in CVB3-induced myocarditis, which was paralleled with a reduction in cardiac apoptosis, cardiomyocyte damage, left ventricular tumour necrosis factor-? mRNA expression, and cardiac mononuclear cell activation. Mesenchymal stem cells reduced the CVB3-induced CD4- and CD8- T cell activation in an NO-dependent way and required IFN-? priming. CONCLUSION: We conclude that MSCs improve murine acute CVB3-induced myocarditis via their anti-apoptotic and immunomodulatory properties, which occur in an NO-dependent manner and require priming via IFN-?.
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Project description:Mesenchymal stromal cell (MSC) application in Coxsackievirus B3 (CVB3)-induced myocarditis reduces myocardial inflammation and fibrosis, exerts prominent extra-cardiac immunomodulation, and improves heart function. Although the abovementioned findings demonstrate the benefit of MSC application, the mechanism of the MSC immunomodulatory effects leading to a final cardioprotective outcome in viral myocarditis remains poorly understood. Monocytes are known to be a trigger of myocardial tissue inflammation. The present study aims at investigating the direct effect of MSC on the mobilization and trafficking of monocytes to the heart in CVB3-induced myocarditis. One day post CVB3 infection, C57BL/6 mice were intravenously injected with 1 x 106 MSC and sacrificed 6 days later for molecular biology and flow cytometry analysis. MSC application reduced the severity of myocarditis, and heart and blood pro-inflammatory Ly6Chigh and Ly6Cmiddle monocytes, while those were retained in the spleen. Anti-inflammatory Ly6Clow monocytes increased in the blood, heart, and spleen of MSC-treated CVB3 mice. CVB3 infection induced splenic myelopoiesis, while MSC application slightly diminished the spleen myelopoietic activity in CVB3 mice. Left ventricular (LV) mRNA expression of the chemokines monocyte chemotactic protein-1 (MCP)-1, MCP-3, CCL5, the adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, the pro-inflammatory cytokines interleukin-6, interleukin-12, tumor necrosis factor-α, the pro-fibrotic transforming growth factorβ1, and circulating MCP-1 and MCP-3 levels decreased in CVB3 MSC mice, while LV stromal cell-derived factor-1α RNA expression and systemic levels of fractalkine were increased in CVB3 MSC mice. MSC application in CVB3-induced myocarditis modulates monocytes trafficking to the heart and could be a promising strategy for the resolution of cardiac inflammation and prevention of the disease progression. Stem Cells Translational Medicine 2017;6:1249-1261.
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Project description:IntroductionCoxsackievirus B3 (CVB3) is known to induce acute and chronic myocarditis. Most infections are clinically unapparent but some patients suffer from ventricular arrhythmias (VA) and sudden cardiac death (SCD). Studies showed that acute CVB3 infection may cause impaired function of cardiac ion channels, creating a proarrhythmic substrate. However, it is unknown whether low level CVB3+ expression in myocytes may cause altered cardiac electrophysiology leading to VA.MethodsCellular electrophysiology was used to analyze cellular action potentials (APs) and occurrence of afterdepolarizations from isolated cardiomyocytes of wildtype (WT) and transgenic CVB3ΔVP0 (CVB3+) mice. Further, we studied surface ECGs, monophasic APs, ventricular effective refractory period (VERP) and inducibility of VAs in Langendorff-perfused whole hearts. All used cardiomyocytes and whole hearts originated from male mice.ResultsCellular action potential duration (APD) in WT and CVB3+ myocytes was unchanged. No difference in mean occurrence or amplitude of afterdepolarizations in WT and CVB3+ myocytes was found. Interestingly, resting membrane potential in CVB3+ myocytes was significantly hyperpolarized (WT: -90.0±2.2 mV, n = 7; CVB3+: -114.1±3.0 mV, n = 14; p<0.005). Consistently, in Langendorff-perfused hearts, APDs were also not different between WT and CVB3+ whole hearts. Within both groups, we found a heart rate dependent shortening of ADP90 with increasing heart rate in Langendorff-perfused hearts. VERP was significantly prolonged in CVB3+ hearts compared to WT (WT: 36.0±2.7 ms, n = 5; CVB3+: 47.0±2.0 ms, n = 7; p = 0.018). Resting heart rate (HR) in Langendorff-perfused hearts was not significantly different between both genotypes. Electrical pacing protocols induced no VA in WT and CVB3+ hearts.ConclusionIn CVB3+ mice, prolonged ventricular refractoriness and hyperpolarized resting membrane potentials in presence of unchanged APD were observed, suggesting that low level CVB3 expression does not promote VA by altered cardiac electrophysiology in this type of chronic myocarditis. These findings may suggest that other mechanisms such as chronic myocardial inflammation or fibrosis may account for arrhythmias observed in patients with chronic enteroviral myocarditis.
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Project description:To determine the cause of a 2008 outbreak of aseptic meningitis in Shandong Province, China, we analyzed samples from outbreak patients and coxsackievirus B3 samples collected during 1990-2010 surveillance. The cause of the outbreak was coxsackievirus B3, genogroup D. Frequent travel might increase importation of other coxsackievirus B3 genogroups.
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