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. 2021 Feb;36(1):61-74.
doi: 10.1007/s12250-020-00266-7. Epub 2020 Jul 28.

Genetic Variation of Multiple Serotypes of Enteroviruses Associated with Hand, Foot and Mouth Disease in Southern China

Yonghong Zhou  1 , Le Van Tan  2 , Kaiwei Luo  3 , Qiaohong Liao  1   4 , Lili Wang  1 , Qi Qiu  1 , Gang Zou  5 , Ping Liu  6 , Nguyen To Anh  2 , Nguyen Thi Thu Hong  2 , Min He  6 , Xiaoman Wei  7 , Shuanbao Yu  4 , Tommy Tsan-Yuk Lam  8 , Jie Cui  9 , H Rogier van Doorn  2   10 , Hongjie Yu  11
Affiliations

Genetic Variation of Multiple Serotypes of Enteroviruses Associated with Hand, Foot and Mouth Disease in Southern China

Yonghong Zhou et al. Virol Sin. 2021 Feb.

Abstract

Enteroviruses (EVs) species A are a major public health issue in the Asia-Pacific region and cause frequent epidemics of hand, foot and mouth disease (HFMD) in China. Mild infections are common in children; however, HFMD can also cause severe illness that affects the central nervous system. To molecularly characterize EVs, a prospective HFMD virological surveillance program was performed in China between 2013 and 2016. Throat swabs, rectal swabs and stool samples were collected from suspected HFMD patients at participating hospitals. EVs were detected using generic real-time and nested reverse transcription-polymerase chain reactions (RT-PCRs). Then, the complete VP1 regions of enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16) and CVA6 were sequenced to analyze amino acid changes and construct a viral molecular phylogeny. Of the 2836 enrolled HFMD patients, 2,517 (89%) were EV positive. The most frequently detected EVs were CVA16 (32.5%, 819), CVA6 (31.2%, 785), and EV-A71 (20.4%, 514). The subgenogroups CVA16_B1b, CVA6_D3a and EV-A71_C4a were predominant in China and recombination was not observed in the VP1 region. Sequence analysis revealed amino acid variations at the 30, 29 and 44 positions in the VP1 region of EV-A71, CVA16 and CVA6 (compared to the respective prototype strains BrCr, G10 and Gdula), respectively. Furthermore, in 21 of 24 (87.5%) identified EV-A71 samples, a known amino acid substitution (D31N) that may enhance neurovirulence was detected. Our study provides insights about the genetic characteristics of common HFMD-associated EVs. However, the emergence and virulence of the described mutations require further investigation.

Keywords: Coxsackievirus A16 (CVA16); Coxsackievirus A6 (CVA6); Enterovirus A71 (EV-A71); Enteroviruses (EVs); Hand, foot and mouth disease (HFMD).

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Conflict of interest statement

HJY has received investigator-initiated research funding from Sanofi Pasteur, GlaxoSmithKline, and Yichang HEC Changjiang Pharmaceutical Company, none of which is related to HFMD and enteroviruses.

Figures

Fig. 1
Fig. 1
Distribution of EV serotypes found in Anhua County, China, October 2013–September 2016. A Distribution of EV-A71, CVA16 and CVA6 HFMD in Anhua County, China, October 2013–September 2016. Total monthly numbers, samples planned for VP1 sequencing and successfully sequenced of B EV-A71, C CVA16, and D CVA6.
Fig. 2
Fig. 2
Phylogenetic analyses of the entire VP1 sequences (891 bp) of EV-A71 from Anhua County based on ML methods. The tree was rooted on genotype A of the EV-A71 strain. The branches of sequences are color-coded according to the EV-A71 lineage. The names of the study sequences are colored in green; the reference strains are uncolored. Bootstrap values > 70% are shown on the branches. The phylogenetic tree indicates that evolutionary branch C4a was responsible for infections in Anhua County during 2013–2016.
Fig. 3
Fig. 3
Phylogenetic analyses of the entire VP1 sequences (891 bp) of CVA16 from Anhua County based on ML methods. The tree was rooted on genotype A of CVA16 strain. The branches of sequences are color-coded according to the CVA16 lineage. The names of the study sequences are colored in green; the reference strains are uncolored. Bootstrap values > 70% were shown on the branches. The phylogenetic tree indicates that evolutionary branch B1b was responsible for infections in Anhua County during 2013–2016.
Fig. 4
Fig. 4
Phylogenetic analyses of the entire VP1 sequences (891 bp) of CVA6 from Anhua County based on ML methods. The tree was rooted on genotype A of CVA6 strain. The branches of sequences are color-coded according to the CVA6 lineage. The names of the study sequences are colored in green; the reference strains are uncolored. Bootstrap values > 70% were shown on the branches. The phylogenetic tree indicates that evolutionary branch D3a was responsible for infections in Anhua County during 2013–2016.
Fig. 5
Fig. 5
Variations were found in EV-A71 (C4a) of our study. “-” indicates matching to the U22521/US/1970 (EV-A71 prototype strain, genotype A, BrCr type-strain). Variations potentially associated with major neutralizing/antigenicity epitopes are indicated in red. BC loop regions are indicated in green, EF loop regions are indicated in orange.
Fig. 6
Fig. 6
Variations were found in CVA16 (B1b) of our study. “-” indicates matching to the U05876/ZA/1951 (CVA16 prototype strain, genotype A, G10 type-strain). Variations potentially associated with major neutralizing/antigenicity epitopes are indicated in red and GH loop regions are indicated in blue.
Fig. 7
Fig. 7
Variations were found in CVA6 (D3a) of our study. “-” indicates matching to the AY421764/US/1949 (CVA6 prototype strain, genotype A, Gdula type-strain). Variations potentially associated with major neutralizing/antigenicity epitopes are indicated in red. BC loop regions are indicated in green, EF loop regions are indicated in orange and GH loop regions are indicated in blue.
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