Viral determinants that drive Enterovirus-A71 fitness and virulence

Ang, Pei Yi; Chong, Connie Wan Hui; Alonso, Sylvie

doi:10.1080/22221751.2021.1906754

Cited by 22 publications

(10 citation statements)

References 77 publications

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“…We also have demonstrated a higher variation among CVB5 sequences with a potential impact on the three-dimensional protein structure that can be critical for CVB5 neurovirulence and resistance to antibody neutralization. Sequence analyses have led to the identification of a number of viral determinants in enterovirus associated with viral fitness and virulence [ 47 ]. Many of these determinants consist of amino acid residues located in the VP1 protein, affecting the early events of virus-host interaction.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Coxsackievirus B5 Infections in the Central Nervous System in Brazil: Insights into Molecular Epidemiology and Genetic Diversity

Machado

Gomes-Neto

Oliveira

et al. 2022

Viruses

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Coxsackievirus B5 (CVB5) is one of the most prevalent enteroviruses types in humans and causes annual epidemics worldwide. In the present study, we explored viral genetic diversity, molecular and epidemiological aspects of CVB5 obtained from cerebrospinal fluid and stool samples of patients with aseptic meningitis or acute flaccid paralysis, information that is still scarce in Brazil. From 2005 to 2018, 57 isolates of CVB5 were identified in the scope of the Brazilian Poliomyelitis Surveillance Program. Phylogenetic analyses of VP1 sequences revealed the circulation of two CVB5 genogroups, with genogroup B circulating until 2017, further replaced by genogroup A. Network analysis based on deduced amino acid sequences showed important substitutions in residues known to play critical roles in viral host tropism, cell entry, and viral antigenicity. Amino acid substitutions were investigated by the Protein Variation Effect Analyzer (PROVEAN) tool, which revealed two deleterious substitutions: T130N and T130A. To the best of our knowledge, this is the first report to use in silico approaches to determine the putative impact of amino acid substitutions on the CVB5 capsid structure. This work provides valuable information on CVB5 diversity associated with central nervous system (CNS) infections, highlighting the importance of evaluating the biological impact of certain amino acids substitutions associated with epidemiological and structural analyses.

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Section: Discussionmentioning

confidence: 99%

Analysis of Coxsackievirus B5 Infections in the Central Nervous System in Brazil: Insights into Molecular Epidemiology and Genetic Diversity

Machado

Gomes-Neto

Oliveira

et al. 2022

Viruses

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“…EV-A71, as an RNA virus, has a high mutation rate and exists as a quasispecies ( 38 – 40 ). During in vitro adaptation, it can evolve into different cell-adapted mutants or populations with various phenotypes.…”

Section: Discussionmentioning

confidence: 99%

A Novel Attenuated Enterovirus A71 Mutant with VP1-V238A,K244R Exhibits Reduced Efficiency of Cell Entry/Exit and Augmented Binding Affinity to Sulfated Glycans

Meng

Wong

Chua

2021

J Virol

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Enterovirus A71 (EV-A71) is one of the major etiological agents of hand, foot, and mouth disease, and its infection occasionally leads to fatal neurological complications in children. However, only inactivated whole virus vaccines against EV-A71 are commercially available in Mainland China. Furthermore, the mechanisms underlying the infectivity and pathogenesis of EV-A71 remain to be better understood. By adaptation of an EV-A71 B5 strain in monkey Vero cells in the presence of brilliant black BN (E151), an anti-EV-A71 agent, a double mutant with VP1-V238A,K244R emerged to be E151 enhanced infection. The growth of reverse genetics (RG) mutant RG/B5-VP1-V238A,K244R (RG/B5-AR) was promoted by E151 in Vero cells, but inhibited in other human and murine cells; while its parental wild type RG/B5-wt was strongly prevented by E151 from infection in all tested cells. In the absence of E151, RG/B5-AR exhibited defective cell entry/exit, resulting in reduced viral transmission and growth in vitro . It had augmented binding affinity to sulfated glycans, cells and tissue/organs, which probably functioned as decoys to restrict viral dissemination and infection. RG/B5-AR was also attenuated with 355 times higher 50% lethal dose and shorter timing of virus clearance than RG/B5-wt in suckling AG129 mice. It, however, remained highly immunogenic in adult AG129 mice to protect their suckling mice from lethal EV-A71 challenges through maternal neutralizing antibodies. Overall, discovery of the attenuated mutant RG/B5-AR contributes to better understanding of virulence determinants of EV-A71 and further development of novel vaccines against EV-A71. Importance Enterovirus A71 (EV-A71) is highly contagious in children and has been responsible for thousands of deaths in Asia-Pacific region since 1990s. Unfortunately, the virulence determinants and pathogenesis of EV-A71 are not fully clear. We discovered that a novel EV-A71 mutant VP1-V238A,K244R showed growth attenuation with reduced efficiency of cell entry/exit. In Vero cell line which has been approved for manufacturing EV-A71 vaccines, the growth defects of the mutant were compensated by a food dye brilliant black BN. The mutant was also with augmented binding affinity to sulfated glycans and other cellular components which probably restricted the viral infection and dissemination. Therefore, it was virulence attenuated in a mouse model but still retained its immunogenicity. Our findings suggest the mutant as a promising vaccine candidate against EV-A71 infection.

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“…Finally, hand, foot, and mouth disease (HFMD) is usually a mild childhood disease caused mainly by coxsackievirus A16 and enterovirus A71 (EV-A71). In 2018, intra- and inter-typic recombination events amongst co-circulating EV-A71 strains contributed to the outbreak and epidemic of HFMD in the Western Pacific countries ( Ang et al, 2021 ).…”

Section: Consequences Of Virus Recombinationmentioning

confidence: 99%

Recombination in Positive-Strand RNA Viruses

et al. 2022

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RNA recombination is a major driver of genetic shifts tightly linked to the evolution of RNA viruses. Genomic recombination contributes substantially to the emergence of new viral lineages, expansion in host tropism, adaptations to new environments, and virulence and pathogenesis. Here, we review some of the recent progress that has advanced our understanding of recombination in positive-strand RNA viruses, including recombination triggers and the mechanisms behind them. The study of RNA recombination aids in predicting the probability and outcome of viral recombination events, and in the design of viruses with reduced recombination frequency as candidates for the development of live attenuated vaccines. Surveillance of viral recombination should remain a priority in the detection of emergent viral strains, a goal that can only be accomplished by expanding our understanding of how these events are triggered and regulated.

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Viral determinants that drive Enterovirus-A71 fitness and virulence

Cited by 22 publications

References 77 publications

Analysis of Coxsackievirus B5 Infections in the Central Nervous System in Brazil: Insights into Molecular Epidemiology and Genetic Diversity

Analysis of Coxsackievirus B5 Infections in the Central Nervous System in Brazil: Insights into Molecular Epidemiology and Genetic Diversity

A Novel Attenuated Enterovirus A71 Mutant with VP1-V238A,K244R Exhibits Reduced Efficiency of Cell Entry/Exit and Augmented Binding Affinity to Sulfated Glycans

Recombination in Positive-Strand RNA Viruses

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