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Coxsackievirus B4: an underestimated pathogen associated with a hand, foot, and mouth disease outbreak

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Abstract

In order to discover the causes of a coxsackievirus B4 (CV-B4)-associated hand, foot, and mouth disease (HFMD) outbreak and to study the evolutionary characteristics of the virus, we sequenced isolates obtained during an outbreak for comparative analysis with previously sequenced strains. Phylogenetic and evolutionary dynamics analysis was performed to examine the genetic characteristics of CV-B4 in China and worldwide. Phylogenetic analysis showed that CV-B4 originated from a common ancestor in Shandong. CV-B4 strains isolated worldwide could be classified into genotypes A–E based on the sequence of the VP1 region. All CV-B4 strains in China belonged to genotype E. The global population diversity of CV-B4 fluctuated substantially over time, and CV-B4 isolated in China accounted for a significant increase in the diversity of CV-B4. The average nucleotide substitution rate in VP1 of Chinese CV-B4 (5.20 × 10-3 substitutions/site/year) was slightly higher than that of global CV-B4 (4.82 × 10-3 substitutions/site/year). This study is the first to investigate the evolutionary dynamics of CV-B4 and its association with an HFMD outbreak. These findings explain both the 2011 outbreak and the global increase in CV-B4 diversity. In addition to improving our understanding of a major outbreak, these findings provide a basis for the development of surveillance strategies.

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The 35 CV-B4 VP1 sequences determined in this study have been deposited in the GenBank database under Accession Numbers MT109013–MT109047.

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Acknowledgements

We would like to acknowledge the staff of the Shandong Center for Disease Control and Prevention for collecting clinical samples.

Funding

This study was supported by the National Key Technology R&D Program of China (Project Nos. 2017ZX10104001, 2018ZX10713002, 2018ZX10711001, and 2018ZX10101002-005-008, 2018ZX10101002-004-006, 2018ZX10101002-001-003, 2018ZX10201002-003-003), and the Beijing Natural Science Foundation (Project No. L192014). The funding body was not involved in the design of the study, clinical sample collection, data analysis and interpretation, or writing of the manuscript.

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Author notes

  1. Jinbo Xiao and Jianxing Wang contributed equally to this manuscript.

  2. Yong Zhang and Xianjun Wang contributed equally to this manuscript.

Authors and Affiliations

  1. WHO WPRO Regional Polio Reference Laboratory, National Laboratory for Poliomyelitis, National Health Commission Key Laboratory for Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Changping District, Beijing, People’s Republic of China

    Jinbo Xiao, Yong Zhang, Huanhuan Lu, Zhenzhi Han, Yang Song, Dongmei Yan, Shuangli Zhu & Wenbo Xu

  2. Shandong Center for Disease Control and Prevention, Jinan, Shandong, People’s Republic of China

    Jianxing Wang, Dapeng Sun, Yaowen Pei & Xianjun Wang

  3. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Beijing, People’s Republic of China

    Yong Zhang & Wenbo Xu

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  1. Jinbo Xiao
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Contributions

JX studied the pathogens, analyzed the critical bioinformation, drafted the manuscript, and prepared all the tables and figures. JW investigated the outbreak, collected specimens, and identified the pathogens. YZ and XW conceived and designed the experiments, supervised and guided the experiments, and revised the manuscript. DS, HL, ZH, YS, DY, and SZ conducted part of the experiments. YP and WX analyzed the data. All authors read the manuscript.

Corresponding authors

Correspondence to Yong Zhang or Xianjun Wang.

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The authors declare that no competing interests exist.

Ethics approval and consent to participate

This study was approved by the Ethics Review Committee of the National Institute for Viral Diseases Control and Prevention, Chinese Center for Disease Control and Prevention. Written informed consent for the use of clinical samples was obtained from all individuals, including written informed consent from guardians of children.

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Handling Editor: Akbar Dastjerdi.

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Xiao, J., Wang, J., Zhang, Y. et al. Coxsackievirus B4: an underestimated pathogen associated with a hand, foot, and mouth disease outbreak. Arch Virol 166, 2225–2234 (2021). https://doi.org/10.1007/s00705-021-05128-5

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