Skip to main content

Molecular Epidemiology of Echovirus 18 Circulating in Mainland China from 2015 to 2016


Echovirus 18 (E18), a serotype of Enterovirus B (EV-B) species, is an important pathogen in aseptic meningitis. E18 had rarely been detected in mainland China, but became the predominant pathogen associated with viral encephalitis (VE) and meningitis in Hebei province for the first time in 2015. To investigate the molecular epidemiology and genetic characteristics of E18 in mainland China, sixteen E18 strains from patient throat swabs with hand, foot, and mouth disease (HFMD) in six provinces in China collected between 2015 and 2016, and four E18 strains isolated from 18 patient cerebrospinal fluid specimens with VE in Hebei Province in 2015 were obtained and sequenced. Combined with the sequences from the GenBank database, we performed an extensive genetic analysis. Phylogenetic analysis of VP1 gene sequences revealed that all E18 strains from mainland China after 2015 belonged to subgenotype C2. There were no obvious specific differences in phylogenetic and variation analyses of E18 genome sequences between HFMD and VE/meningitis strains. Potential multiple recombination may have occurred in the 5′-untranslated region and in the P2 and P3 nonstructural protein-encoding regions of E18 strains from China. The current E18 strains were potential multiple-recombinant viruses. Overall, these findings supported that E18 caused HFMD, VE, and meningitis, although there were no significant associations between clinical features and viral genomic characteristics.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  • Abedi GR, Watson JT, Pham H, Nix WA, Oberste MS, Gerber SI (2015) Enterovirus and human Parechovirus surveillance—United States, 2009–2013. MMWR Morb Mortal Wkly Rep 64:940–943

    Article  PubMed  Google Scholar 

  • Andersson P, Edman K, Lindberg AM (2002) Molecular analysis of the echovirus 18 prototype: evidence of interserotypic recombination with echovirus 9. Virus Res 85:71–83

    Article  CAS  PubMed  Google Scholar 

  • Chen P, Song Z, Qi Y, Feng X, Xu N, Sun Y, Wu X, Yao X, Mao Q, Li X, Dong W, Wan X, Huang N, Shen X, Liang Z, Li W (2012) Molecular determinants of enterovirus 71 viral entry: cleft around GLN-172 on VP1 protein interacts with variable region on scavenge receptor B 2. J Biol Chem 287:6406–6420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Li J, Guo J, Xu W, Sun S, Xie Z (2017) An outbreak of echovirus 18 encephalitis/meningitis in children in Hebei Province, China, 2015. Emerg Microbes Infect 6:e54

    PubMed  PubMed Central  Google Scholar 

  • Drummond AJ, Suchard MA, Xie D, Rambaut A (2012) Bayesian phylogenetics with BEAUti and the BEAST 1.7. Mol Biol Evol 29:1969–1973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Y, Lin F, Chipman PR, Bator CM, Baker TS, Shoham M, Kuhn RJ, Medof ME, Rossmann MG (2002) Structure of decay-accelerating factor bound to echovirus 7: a virus-receptor complex. Proc Natl Acad Sci USA 99:10325–10329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krumbholz A, Egerer R, Braun H, Schmidtke M, Rimek D, Kroh C, Hennig B, Groth M, Sauerbrei A, Zell R (2016) Analysis of an echovirus 18 outbreak in Thuringia, Germany: insights into the molecular epidemiology and evolution of several enterovirus species B members. Med Microbiol Immunol 205:471–483.

    Article  PubMed  Google Scholar 

  • Lole KS, Bollinger RC, Paranjape RS, Gadkari D, Kulkarni SS, Novak NG, Ingersoll R, Sheppard HW, Ray SC (1999) Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination. J Virol 73:152–160

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lukashev AN (2005) Role of recombination in evolution of enteroviruses. Rev Med Virol 15:157–167

    Article  CAS  PubMed  Google Scholar 

  • Lukashev AN, Lashkevich VA, Ivanova OE, Koroleva GA, Hinkkanen AE, Ilonen J (2005) Recombination in circulating human enterovirus B: independent evolution of structural and non-structural genome regions. J Gen Virol 86:3281–3290

    Article  CAS  PubMed  Google Scholar 

  • Lukashev AN, Shumilina EY, Belalov IS, Ivanova OE, Eremeeva TP, Reznik VI, Trotsenko OE, Drexler JF, Drosten C (2014) Recombination strategies and evolutionary dynamics of the human enterovirus A global gene pool. J Gen Virol 95:868–873

    Article  CAS  PubMed  Google Scholar 

  • Miyamura K, Yamashita K, Yamadera S, Kato N, Akatsuka M, Yamazaki S (1990) An epidemic of echovirus 18 in 1988 in Japan–high association with clinical manifestation of exanthem. A report of the National Epidemiological Surveillance of Infectious Agents in Japan. Jpn J Med Sci Biol 43:51–58

    Article  CAS  PubMed  Google Scholar 

  • Oberste MS, Maher K, Pallansch MA (2004) Evidence for frequent recombination within species human enterovirus B based on complete genomic sequences of all thirty-seven serotypes. J Virol 78:855–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park K, Yeo S, Baek K, Cheon D, Choi Y, Park J, Lee S (2011) Molecular characterization and antiviral activity test of common drugs against echovirus 18 isolated in Korea. Virol J 8:516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Posada D, Crandall KA (1998) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817–818

    Article  CAS  PubMed  Google Scholar 

  • Reimann BY, Zell R, Kandolf R (1991) Mapping of a neutralizing antigenic site of Coxsackievirus B4 by construction of an antigen chimera. J Virol 65:3475–3480

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rezaikin AV, Novoselov AV, Sergeev AG, Fadeyev FA, Lebedev SV (2009) Two clusters of mutations map distinct receptor-binding sites of echovirus 11 for the decay-accelerating factor (CD55) and for canyon-binding receptors. Virus Res 145:74–79

    Article  CAS  PubMed  Google Scholar 

  • Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai HP, Huang SW, Wu FL, Kuo PH, Wang SM, Liu CC, Su IJ, Wang JR (2011) An echovirus 18-associated outbreak of aseptic meningitis in Taiwan: epidemiology and diagnostic and genetic aspects. J Med Microbiol 60:1360–1365

    Article  PubMed  Google Scholar 

  • Turabelidze G, Lin M, Butler C, Fick F, Russo T (2009) Outbreak of echovirus 18 meningitis in a rural Missouri community. Mo Med 106:420–424

    PubMed  Google Scholar 

  • Wang SM, Ho TS, Shen CF, Wang JR, Liu CC (2011) Echovirus 18 meningitis in southern Taiwan. Pediatr Infect Dis J 30:259–260

    Article  PubMed  Google Scholar 

  • Zhang Y, Wang J, Guo W, Wang H, Zhu S, Wang D, Bai R, Li X, Yan D, Wang H, Zhang Y, Zhu Z, Tan X, An H, Xu A, Xu W (2011) Emergence and transmission pathways of rapidly evolving evolutionary branch C4a strains of human enterovirus 71 in the Central Plain of China. PLoS ONE 6:e27895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Zhao Y, Liu H, Sun H, Huang X, Yang Z, Ma S (2017) Molecular characterization of two novel echovirus 18 recombinants associated with hand–foot–mouth disease. Sci Rep 7:8448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng H, Zhang Y, Liu L, Lu J, Guo X, Li H, Zeng H, Fang L, Xu W, Ke C (2016) Isolation and Characterization of a Highly Mutated Chinese Isolate of Enterovirus B84 from a Patient with Acute Flaccid Paralysis. Sci Rep 6:31059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (Grant Nos. 2017ZX10104001-005-010 and 2017ZX10103004-004); Beijing Natural Science Foundation (Grant No. 7184208); Capital Clinical Feature Project of Beijing Technology Program (Grant No. Z151100004015046); Basic and Clinical Research Cooperation Project of Capital Medical University (Grant No. 17JL11); and Research Training Fund of Capital Medical University (Grant No. PYZ2017012). The sponsors had no role in the study design, data analysis, manuscript preparation, or publishing decision.

Author information

Authors and Affiliations



XC, ZX, and WX conceived and designed the experiments; XC, TJ, and JG performed the experiments; XC and WW analyzed the data; XC and ZX contributed to the writing of the manuscript. All authors reviewed and approved the final manuscript for submission.

Corresponding authors

Correspondence to Wenbo Xu or Zhengde Xie.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Animal and Human Rights Statement

The study was approved by the Medical Ethics Committee of Beijing Children’s Hospital, Capital Medical University (Permit No. 2015-8). Informed consents were obtained from legal guardians of all patients prior to the collection of CSF and throat swab samples.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 204 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Ji, T., Guo, J. et al. Molecular Epidemiology of Echovirus 18 Circulating in Mainland China from 2015 to 2016. Virol. Sin. 34, 50–58 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Genetic characteristics
  • Echovirus 18 (E18)
  • Genome
  • Enterovirus
  • Recombination