Attenuating Mutations in Coxsackievirus B3 Map to a Conformational Epitope That Comprises the Puff Region of VP2 and the Knob of VP3

Stadnick, Ellamae; Dan, Meixia; Sadeghi, Assai Mir Mohammad; Chantler, J. K.

doi:10.1128/jvi.78.24.13987-14002.2004

Cited by 37 publications

(47 citation statements)

References 46 publications

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“…13 Remarkably, many aspects of viral myocarditis may be recapitulated in experimental autoimmune models as induced by cardiac myosin and an adjuvant. 14 Pathological outcome of CVB3-induced myocarditis is determined by a complex interplay between viral [15][16][17][18] and host factors. At least two host proteins, decay accelerating factor (DAF) 19 and coxsackievirus-adenovirus receptor (CAR), 20,21 function as receptors for virus attachment and entry through binding with virus capsid proteins.…”

Section: Introductionmentioning

confidence: 99%

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

et al. 2007

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The pathogenesis of viral myocarditis is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a model of infection with coxsackievirus B3 (CVB3) to characterize the contribution of host genetics to viral myocarditis in mice of different genetic backgrounds but with a common H2 haplotype: A/J and B10.A-H2 a .Here we have used Evans blue dye as a quantitative biomarker for susceptibility to CVB3-induced myocarditis in addition to histopathological semiquantitative measures. We have found evidence of linkage between susceptibility to viral myocarditis and three loci. A locus on chromosome 1 centered on D1Mit200 was linked to sarcolemmal disruption in males (P ¼ 0.00005), a second locus on chromosome 4 centered on D4Mit81 was also linked to sarcolemmal disruption in males (P ¼ 0.0022). A third locus on distal chromosome 3 centered on D3Mit19 was linked to myocardial infiltration, with a logarithm of odds (LOD) score of 4.7 (P ¼ 0.0045), as well as sarcolemmal disruption in females (P ¼ 0.0015). These results provide strong evidence for the presence of loci contributing to the susceptibility of mice to viral myocarditis.

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Section: Introductionmentioning

confidence: 99%

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

et al. 2007

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“…Like the Puff region of VP2, the Knob region of VP3 is known to contain a major neutralization site for both poliovirus and rhinovirus [30,32]. Furthermore, mutations in the VP3 Knob region have been suggested to have a role in the CVB3-induced cardiovirulence [31]. Whether or not the nonsynonymous mutations detected in the capsid region of the three clinical isolates play a role in virulence and pathogenesis of enterovirus infection, needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The three clinical isolates in this study had amino acid substitutions in the Puff region of the VP2 protein. Amino acid substitutions in the Puff region of CVB3 VP2 protein were previously linked to cardiovirulence [31]. Like the Puff region of VP2, the Knob region of VP3 is known to contain a major neutralization site for both poliovirus and rhinovirus [30,32].…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of three enteroviral strains isolated in Kuwait from young children with serious conditions

Chehadeh

Ali

Maimoona

2017

J Infect Dev Ctries

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Introduction: Human enteroviruses are single stranded RNA viruses associated with many serious diseases such as encephalitis and myocarditis. They consist of up to 100 immunologically and genetically distinct types. Three enteroviral isolates, 2104, 3936 and 3988, were previously isolated from patients with neurological disorders or sepsis-like illness. In this study, the molecular characterization of the isolates was investigated. Methodology: A full genome sequencing was performed by Sanger method, followed by phylogenetic and bootscanning analyses. A detailed analysis of genetic differences between the clinical and prototype isolates were investigated by mapping polymorphisms at nucleotide and amino acid levels, and by comparing RNA secondary structure in the noncoding regions. Results: Based on the phylogenetic analysis of the VP1 gene and complete genome, 2104 was typed as coxsackievirus B1, 3936 as coxsackievirus B5, and 3988 as echovirus 7. Similarity and bootscan plots provided support for intra-and intertypic recombination with crossover points occurring mainly along the nonstructural coding regions of the isolates. A sequence divergence of 12 to 14% was detected in the 5'-noncoding region between the clinical isolates and their corresponding prototype strains. Synonymous and nonsynonymous substitutions could be also mapped to different coding regions of the isolates, including those coding for the Puff, Knob and the hydrophobic pocket of the capsid. Examination of relative frequencies of synonymous and nonsynonymous substitutions in different coding regions of enteroviral isolates showed no evidence for selective pressure. Conclusion: The results provided a better understanding of the genetic variations, evolution and adaptation of enteroviruses in Kuwait.

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“…The construction of the infectious clones pCVB3(KR) and pCVB3(EG) was previously described (26). The plasmid pCVB3(KR) has a single mutation of A to G at nucleotide 1421, resulting in a lysine (K)-to-arginine (R) substitution at amino acid 158 of the capsid protein VP2 (K2158R), while pCVB3(EG) contains a single mutation of A to G at nucleotide 1916, resulting in a glutamic acid (E)-to-glycine (G) substitution at amino acid 60 of VP3 (E3060G).…”

Section: Methodsmentioning

confidence: 99%

“…In 1996, a single amino acid substitution in the puff region of VP2 (asparagine to aspartate at amino acid 165) was found to reduce the myocardicity of a CVB3 mutant, H310A1 (14). Recently, we identified two mutations in the capsid proteins that affected cardiovirulence in studies of a panel of "escape" mutants (EMs 1 to 10) derived by treating a parental myocarditic strain, CVB3(RK), with a highly neutralizing monoclonal antibody (26). Two mutations were identified that were associated with both a lack of neutralization by the monoclonal antibody and reduced cardiovirulence.…”

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confidence: 99%

A Genetically Engineered Attenuated Coxsackievirus B3 Strain Protects Mice against Lethal Infection

Dan

Chantler

2005

J Virol

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Coxsackievirus B3 (CVB3) is a common human pathogen that is endemic throughout the world. There is currently no vaccine available, although the virus is known to be highly lethal to newborns and has been associated with heart disease and pancreatitis in older children and adults. Previously, we showed that the virulence of CVB3 is reduced by a lysine-to-arginine substitution in the capsid protein VP2 (K2168R) or a glutamic acid-to-glycine substitution in VP3 (E3060G). In this report, we show that the double mutant virus CVB3(KR/EG) displays additional attenuation, particularly for the pancreas, in A/J mice. In addition, two other attenuating mutations have been identified in the capsid protein VP1. When either the aspartic acid residue D1155 was replaced with glutamic acid or the proline residue P1126 was replaced with methionine, the resulting mutant also possessed an attenuated phenotype. Moreover, when either of these mutations was incorporated into CVB3(KR/EG), the resulting triple mutant viruses, CVB3(KR/EG/DE) and CVB3(KR/EG/ PM), were completely noncardiovirulent and caused only small foci of damage to the pancreas, even at a high dose. Both triple mutants were found to be immunogenic, and a single injection of young A/J mice with either was found to protect them from a subsequent lethal challenge with wild-type CVB3. These findings indicate that the triple mutants could be exploited for the development of a live attenuated vaccine against CVB3.

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Attenuating Mutations in Coxsackievirus B3 Map to a Conformational Epitope That Comprises the Puff Region of VP2 and the Knob of VP3

Cited by 37 publications

References 46 publications

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

Molecular characterization of three enteroviral strains isolated in Kuwait from young children with serious conditions

A Genetically Engineered Attenuated Coxsackievirus B3 Strain Protects Mice against Lethal Infection

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