Sequence analysis‐based characterization and identification of neurovirulence‐associated variants of 36 EV71 strains from China

Xu, Jun; Wang, Fang; Zhao, Desheng; Liu, Jiang; Su, Hong; Wang, Baolong

doi:10.1002/jmv.25081

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…In PJ201984, P2 region had the lowest variation, whereas had the highest different amino acid substitution. The findings revealed that the variations in P2 region might result in changing protein properties, as documented elsewhere [ 33 ]. Similarly, P3 region tended to be unstable because of the highest variation.…”

Section: Discussionsupporting

confidence: 78%

Molecular characteristics of a coxsackievirus A12 strain in Zhejiang of China, 2019

Lu²,

Wang³

et al. 2022

Virol J

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Background Enterovirus A (EV-A), such as enterovirus A71 (EV-A71), generally causes hand, foot, and mouth disease (HFMD). However, limited studies focused on uncommon enterovirus serotypes such as coxsackievirus A12 (CV-A12). This study aimed to provide evidence to determine the molecular characteristics of a CV-A12 strain isolated in Zhejiang province, China. Methods In routine surveillance of HFMD, we identified a child case with CV-A12 infection in 2019 in Zhejiang province, China. Enterovirus was examined by using real-time reverse transcription-PCR (qRT-PCR). A partial VP1 sequence was amplified to determine the serotype, and then a full-length CV-A12 genome was sequenced. Nucleotide and amino acid similarity was calculated with those CV-A12 strains available in GenBank. Recombination was detected using RDP 4 and SimPlot. Furthermore, phylogenetic analysis was conducted by using BEAST 1.10, and protein modeling was performed with I-TASSER webserver. Results A full-length CV-A12 genome PJ201984 was isolated in a Chinese child with HFMD. The similarities with complete coding sequences of the CV-A12 strains in GenBank ranged between 79.3–100% (nucleotide) and 94.4–100% (amino acid), whereas it was 88.7–100.0% (nucleotide) and 97.2–100% (amino acid) when excluding the CV-A12 prototype strain Texas-12. In PJ201984, amino acid variations were more divergent in P2 and P3 regions than those in P1; the majority of those variations in VP1 (13/15) and VP4 (7/8) were similar to those documented in recently isolated CV-A12 strains in China. Furthermore, recombination was identified in P2 region, which involved a CV-A5 strain collected in China. Phylogenetic analysis revealed that PJ201984 clustered together with multiple CV-A12 strains isolated in China and the Netherlands during 2013–2018, as compared to another cluster consisting of CV-A12 strains in China and France during 2009–2015. Additionally, protein models of VP1 and VP4 in PJ201984 were well predicted to be similar to VP1 protein of EV-A71 and VP4 protein of coxsackievirus A21, respectively. Conclusions The full-length CV-A12 genome was characterized to have common recombination in P2 region and be phylogenetically related to those CV-A12 strains isolated in recent years, suggesting a continual spread in China. It warrants strengthening the routine surveillance for uncommon enterovirus serotypes, particularly on possible recombination and variation.

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Section: Discussionsupporting

confidence: 78%

Molecular characteristics of a coxsackievirus A12 strain in Zhejiang of China, 2019

Lu²,

Wang³

et al. 2022

Virol J

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“…3D protein, which is an RNA dependent RNA polymerase (RdRp), is responsible for regulating the extension of nucleic acid chains during virus replication. 3D protein crystal is a “right hand” conformation, including “finger”, “palm” and “thumb” domains, that different domains have different functions [ 37 ]. Studies have shown that there was potential interaction between 3D and 5′UTR.…”

Section: Discussionmentioning

confidence: 99%

EV71 5’UTR interacts with 3D protein affecting replication through the AKT-mTOR pathway

Xu,

Ma,

Liu

et al. 2024

Virol J

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Background EV71 is one of the important pathogens of Hand-foot-and-mouth disease (HFMD), which causes serious neurological symptoms. Several studies have speculated that there will be interaction between 5′UTR and 3D protein. However, whether 5′UTR interacts with the 3D protein in regulating virus replication has not been clarified. Methods Four 5'UTR mutation sites (nt88C/T, nt90-102-3C, nt157G/A and nt574T/A) and two 3D protein mutation sites (S37N and R142K) were mutated or co-mutated using virulent strains as templates. The replication of these mutant viruses and their effect on autophagy were determined. Results 5'UTR single-point mutant strains, except for EGFP-EV71(nt90-102-3C), triggered replication attenuation. The replication ability of them was weaker than that of the parent strain the virulent strain SDLY107 which is the fatal strain that can cause severe neurological complications. While the replication level of the co-mutant strains showed different characteristics. 5 co-mutant strains with interaction were screened: EGFP-EV71(S37N-nt88C/T), EGFP-EV71(S37N-nt574T/A), EGFP-EV71(R142K-nt574T/A), EGFP-EV71(R142K-nt88C/T), and EGFP-EV71(R142K-nt157G/A). The results showed that the high replicative strains significantly promoted the accumulation of autophagosomes in host cells and hindered the degradation of autolysosomes. The low replicative strains had a low ability to regulate the autophagy of host cells. In addition, the high replicative strains also significantly inhibited the phosphorylation of AKT and mTOR. Conclusions EV71 5'UTR interacted with the 3D protein during virus replication. The co-mutation of S37N and nt88C/T, S37N and nt574T/ A, R142K and nt574T/A induced incomplete autophagy of host cells and promoted virus replication by inhibiting the autophagy pathway AKT-mTOR. The co-mutation of R142K and nt88C/T, and R142K and nt157G/A significantly reduced the inhibitory effect of EV71 on the AKT-mTOR pathway and reduced the replication ability of the virus.

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“…As demonstrated in previous studies in the past few years, certain key amino acid positions on the capsid protein of EV71 determine its replication ability in mice, as well as the susceptibility of mice of different ages to EV71, as well as the virulence of the viruses ( 39 ). As revealed in in-depth studies, certain vital amino acids on the EV71 VP1 protein show a relationship with the mild and severe clinical manifestations of diseases ( 40 ), and the mutations of some amino acid positions on the VP1 may cause neurological symptoms and severe HFMD ( 41 ). The number of cases of severe HFMD attributed to CVA6 have been rising over the past few years ( 42 ), and the mutations of certain amino acid positions on the CVA6 VP1 protein were suggested to correlate with the severity of HFMD ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs

Jiang¹,

Zhang

Lin³

et al. 2021

Front. Immunol.

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Coxsackievirus A6 (CVA6) is recognized as a major enterovirus type that can cause severe hand, foot, and mouth disease and spread widely among children. Vaccines and antiviral drugs may be developed more effectively based on a stable and easy-to-operate CVA6 mouse infection model. In this study, a wild CVA6-W strain was sub-cultured in newborn mice of different ages (in days), for adaptation. Therefore, a CVA6-A mouse-adapted strain capable of stably infecting the mice was generated, and a fatal model was built. As the result indicated, CVA6-A could infect the 10-day-old mice to generate higher levels of IFN-γ, IL-6, and IL-10. The mice infected with CVA6-A were treated with IFN-α1b at a higher dose, with complete protection. Based on this strain, an animal model with active immunization was built to evaluate antiviral protection by active immunization. The three-day-old mice were pre-immunized with inactivated CVA6 thereby generating IgM and IgG antibodies within 7 days that enabled complete protection of the pre-immunized mice following the CVA6 virus challenge. There were eight mutations in the genome of CVA6-A than in that of CVA6-W, possibly attributed to the virulence of CVA6 in mice. Briefly, the CVA6 infection model of the 10-day-old mice built herein, may serve as an applicable preclinical evaluation model for CVA6 antiviral drugs and vaccine study.

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Sequence analysis‐based characterization and identification of neurovirulence‐associated variants of 36 EV71 strains from China

Cited by 5 publications

References 30 publications

Molecular characteristics of a coxsackievirus A12 strain in Zhejiang of China, 2019

Molecular characteristics of a coxsackievirus A12 strain in Zhejiang of China, 2019

EV71 5’UTR interacts with 3D protein affecting replication through the AKT-mTOR pathway

A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs

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