Molecular characteristics of VP1 region of enterovirus 71 strains in China

doi:10.21203/rs.3.rs-26341/v2

Download PDF

Research

Molecular characteristics of VP1 region of enterovirus 71 strains in China

https://doi.org/10.21203/rs.3.rs-26341/v2

This work is licensed under a CC BY 4.0 License

Journal Publication

published 14 Aug, 2020

Read the published version in Gut Pathogens →

You are reading this older preprint version

Read the latest preprint version →

Background: Enterovirus 71 (EV71) is the most commonly implicated as the causative agent of severe and fetal hand, foot, and mouth disease (HFMD) outbreaks.VP1 protein, a capsid protein of EV71, is responsible for the genotype of EV71, which is essential for vaccine development and effectiveness. However, the genotypes of EV71 isolates in China are still not completely clear.

Methods: The VP1 gene sequences of 3712 EV71 virus strains from China, excluding repetitive sequences, and 30 known EV71 genotypes as reference strains, between 1986 and 2019 were obtained from GenBank. A phylogenetic tree, amino acid homology, genetic variation and genotype analysis of the EV71-VP1 protein were performed with MEGA 6.0 software.

Results: The amino acid identity was 88.33%~100% among 3712 EV71 strains that was 93.47%~100% compared with vaccine strain H07, and 93.04%~100% compared with vaccine strains FY7VP5 or FY-23K-B. Since 2000, the prevalent strains of EV71 were mainly the C4 genotype. Among these the C4a subgenotype was predominant, the C4b subgenotype was the second, and other subgenotypes appeared sporadically between 2005 and 2018 in mainland China. The B4 genotype was the main genotype in Taiwan, and the epidemic strains were constantly changing. Some amino acid variations in VP1 of EV71 occurred with high frequencies: A289T (20.99%), H22Q (16.49%), A293S (15.95%), S283T (15.11%), V249I (7.76%), N31D (7.25%), and E98K (6.65%).

Conclusion: The C4 genotype of EV71 in China can match the vaccine, which can effectively control EV71 epidemiology. However, the efficacy of the vaccine strain is partially affected by the continuous change in epidemic strains in Taiwan, China. These studies suggested that the genetic characteristics of the EV71-VP1 region should be continuously monitored, which is critical for epidemic control and vaccine design against EV71 infection in children.

Infectious Diseases

Gastroenterology & Hepatology

Genetic characteristics

Enterovirus 71

VP1

Mutation

Genotype

Enterovirus 71 (EV71) is a common pathogen of hand, foot, and mouth disease in children, and it is also the most important risk factor for severe cases and deaths [1-4]. Some children with hand, foot, and mouth disease (HFMD) can have severe neurological diseases, such as aseptic meningitis, encephalitis and acute delayed paralysis, and develop serious brainstem encephalitis, neurogenic pulmonary edema and even death [5-6]. The surviving children with severe neurological diseases often have irreversible sequelae, seriously threatening the health of children [7-8].

EV71 was first discovered in 1969; the virus was distributed mainly in the Americas, Europe and other countries in sporadic form, and there were outbreaks in some European countries in the 1970s and 1980s [9-10]. After 1997, EV71 began to emerge and spread in Asia, and the Asia-Pacific region is the most prevalent place for EV71. There are reports of EV71 outbreaks in China, Singapore, Malaysia and so on [11-12]. Diseases caused by EV71 infection have been widely prevalent in China since 2007 [13]. Hand, foot and mouth disease (HFMD) pandemics in Linyi city, Shandong Province, and Guangdong, Anhui Province, in 2008 resulted in tens of thousands of childhood infections and dozens of child deaths [14-15].

EV71 virus belongs to the enterovirus genus of the RNA virus family. According to the nucleotide differences in the VP1 region, EV71 can be clustered into three genotypes including genotype A (BrCr) with only one member, B and C, whereas genotype B and C is divided into five subgenotypes, B1-B5 and C1-C5,respectively, and genotype C4 is further subdivided into C4a and C4b [16-18]. In China, the genotype C4 is the main epidemic strain, C4b was the predominant epidemic genotype from 1998 to 2004, and it was mainly the C4a subgenotype after 2004 in mainland China, although Taiwan strains continued to circulate for including C2, B4 and B5 genotypes [19-25]. At present, phase III clinical trials of vaccines from three companies in China have been completed, and the genotypes of their vaccine strains are all C4a subgenotypes [26]. The Vaccine Research and Development Center of National Institutes of Health in Taiwan has also developed an FI-EV71 vaccine based on the B4 subtype (EV71vac), which can cause a robust cross-neutralizing antibody reaction against different EV71 gene subtypes, such as B4, B1, B5 and C4a [26-27].

However, there are many reports on recombination between different genotypes of EV71 [28-31], suggesting that EV71 has high variability and recombination ability, which may lead to the production of new pathogenic strains. Therefore, genome monitoring of EV71 epidemic strains is of great significance for the prevention and control of EV71 epidemics and can guide the application of the EV71 vaccine to a certain extent. In this study, the VP1 sequences of all EV71 viruses registered in GenBank in China from 1996 to 2019 were collected, and the molecular characteristics of genes were analyzed by bioinformatics software to provide a scientific basis for the prevention and control of HFMD epidemics.

1.1 Acquisition of the EV71-VP1 gene sequence

The complete VP1 gene sequences with 891 bp of EV71 strains isolated from children with HFMD from 1986 to December 31, 2019 in China with known collection dates and isolation regions, including mainland China, Hong Kong, Macao and Taiwan, were obtained from the GenBank public database on the National Center for Biotechnology Information (NCBI) PubMed website (http://www.ncbi.nlm.nih.gov/genbank/). A total of 8340 EV71 strains from China were collected from GenBank, consisting of 6572 strains from mainland China, 26 strains from Hong Kong, zero strains from Macao, and 1742 strains from Taiwan. If EV71 strains were isolated the same year and from the same region and had 100% nucleotide homology, only one strain was included. Therefore, a total of 3470 strains from mainland China, 2 strains from Hong Kong, and 1156 strains from Taiwan were removed. Finally, 3712 strains, consisting of 3102 strains from mainland China, 24 strains from Hong Kong, and 586 strains from Taiwan, were retained in this study. The time and geographical distribution of all EV71 isolates are shown in this study (Fig. 1 and 2). The nucleotide sequence of the complete VP1 gene of all virus strains was 891 bp, and Chinese vaccine strains (H07, FY7VP5, and FY-23K-B) and 27 known genotypes of EV71 strains were considered reference sequences that are shown in Table 1.

1.2 Construction of an EV71-VP1 phylogenetic tree and gene sequence analysis

The complete VP1 sequences of EV71 strains were compared by Molecular Evolutionary Genetics Analysis (MEGA) version 6.0 [32]. In brief, a phylogenetic tree of the EV71-VP1 gene was constructed by the adjacency method (neighbor-joining, N-J) with 1000 bootstrap replications, and the homology and variation of the VP1 gene sequences of the EV71 strains were analyzed by MEGA 6.0.in the study.

2.1 Phylogeny and homology analysis of the EV71 VP1 region

A phylogenetic tree of the VP1 amino acid sequence was constructed with 3712 EV71 isolates from China and 30 reference strains (Fig. 3). The amino acid identity was 88.33%~100% among 3712 EV71 strains that was 93.47%~100% compared with vaccine strain H07, and 93.04%~100% compared with vaccine strains FY7VP5 or FY-23K-B. Among these EV71 strains, the C4 genotype accounted for the predominant strains of EV71, and the C4a subgenotype was the most common. Moreover, B4, C4b and C2 were also important genotypes of EV71, and other subgenotypes appeared sporadically.

2.2 Genotypic distribution of EV71 strains in different years in China

Among 3712 strains, the only 6 strains first isolated from China in 1986 were all B3 genotypes. Next, different genotypes/subgenotypes of EV71 were found in China. From 1986 to 2007, there was a small epidemic peak of EV71 in 1998 with the C2 genotype. Moreover, between 1999 and 2003, the B4 genotype was the predominant strain of EV71. Most EV71 strains between 2004 and 2005 were C3 genotypes. From 2006 to 2018, the C4a subgenotype was the most common epidemic strain, and the B4 and C4b genotypes also accounted for a certain proportion of EV71 strains (Table 2 and Fig.4).

Next, the EV71 strains isolated from China including mainland China, Hong Kong, and Taiwan were further analyzed to explore their genotypic distribution in different years. The results indicated that from 2005 to 2018, the C4a subgenotype was absolutely the predominant strain of EV71, the C4b subgenotype was the second, and other subgenotypes appeared sporadically in mainland China. Moreover, among the 24 strains isolated from Hong Kong, there were 10 strains of the C4a subgenotype (1 strain in 2008, 10 strains in 2010, and 1 strain in 2012) and 14 strains of the C4b subgenotype (1 strain in 2008 and 13 strains in 2010). The results for mainland China are shown in Table 3 and Fig.5.

However, the epidemic strains of EV71 in Taiwan from 1986 to 2018 are quite different from those in mainland China, and epidemic strains are not predominantly represented by a single subgenotype but are constantly changing. The first 6 strains isolated from Taiwan, China, in 1986 were all of the B3 genotype. In 1998, C2 was the predominant EV71 genotype in Taiwan. From 1999 to 2003, 2008 to 2009, and 2011 to 2012, the epidemic strains in Taiwan evolved mainly into B4 genotype EV71 strains. Additionally, between 2010 and 2011, C4a was an important genotype (Table 4 and Fig. 6).

2.3 Analysis of amino acid variation of EV71-VP1

The analysis of the common amino acid variation sites in the EV71-VP1 region showed that of the 3712 strains, the major common amino acid site variation was site 289, with a total variation rate of 23.55%, and A289T was the most common variant, accounting for 20.99%. Moreover, 10.24% of strains from mainland China, including Hong Kong, exhibited this variation, and 10.75% of strain from Taiwan also had this variation. There was a total mutation rate of 21.85% at amino acid site 22 in VP1 region. The frequency of the H22Q variation was 16.49%, of which mainland China, including Hong Kong, exhibited 5.50%, and Taiwan exhibited 10.99%; furthermore 23% of the EV71 strains had an H22R mutation. Moreover, the mutation rates of A293S, S283T, V249I, N31D and E98K were 15.95%, 15.11%, 7.76%, 7.76% and 6.65%, respectively. Among the common amino acid variation sites of the EV71-VP1 region, the most common amino acid variation was at site 293, and there were five kinds of amino acid variation, among which the A293S mutation was the most common (Table 5).

It has been reported that the major EV71 strains basically have belonged to the C4 genotype in mainland China since 2004 [18, 33]. In this study, it was found that the epidemic strains of EV71 in mainland China were dominated by the C4 genotype since 2000 and mainly the C4b subgenotype from 2000 to 2004, and the proportion of the C4a subgenotype had increased significantly since 2005. From 2005 to 2018, the C4a subtype was dominant, and the C4b subtype was the second, and other subtypes appeared sporadically, this pattern was similar to previous reports [20, 21, 30, 33]. From 2004 to 2018, most of the EV71 isolates in mainland China were genotype C, and most of them were subtype C4 (especially subtype C4a), while other genotypes occurred sporadically (9 strains of genotype B in 2011, 4 strains of genotype A in 2008, 2 strains of genotype A in 2009, 1 strain of genotype A in 2011 and 1 strain of genotype A in 2012). The immune effectiveness of inactivated vaccines depends mostly on the antigenic correlation between epidemic strains and vaccine strains, which are often best for preventing the infection of the same subtype virus but poor against different subtypes [30]. Recent studies have also shown that the EV71 vaccine (especially in children who receive 2 doses of immunization) can effectively prevent and control childhood EV71-associated HFMD but has no protective effect against coxsackievirus (CV) A6 (CVA-6) or CVA16, and there is no explanation for the effectiveness of other subtypes of EV71 (excluding C4a subtypes) [34]. These studies show that the vaccine research and development for EV71 combined with CVA6 and CVA16 and other multivalent vaccines could better prevent EV71 infection.

Interestingly, this study found that the subtypes of EV71 epidemic strains in Taiwan were mainly B4 genotypes, which were different from those in mainland China, and EV71 epidemic strains are also constantly changing, which is consistent with early reports [26]. A previous study indicated that the FI-EV71 vaccine (EV71vac) based on the B4 genotype from Taiwan, China, was safe and induced a high titer of neutralizing antibodies against EV71 in a human phase 1 clinical trial on adults in 2010 and was highly effective against B1, B5, and C4a strains. However, the titers of neutralizing antibodies against C4b and CVA16 were low in 20% of volunteers, and virus-neutralizing antibodies against the C2 genotype were not detected in 90% of the vaccine recipients [26-27]. These studies indicate that it is necessary to strengthen the monitoring of EV71 genotypes; new multivalent and effective vaccines that can cover local strains should be designed and applied according to the genotypes of local predominant EV71 epidemics to ensure that the vaccine plays a more accurate role in the control of HFMD epidemics.

Some studies have shown that the H22Q mutation in the VP1 protein of EV71 virus can lead to a decrease in the adsorption capacity of the C4 genotype to host cells [35-37]. The amino acid at position 22 of 78.15% of the 3712 strains isolated in China was H (histidine), which suggested that most of the viruses had strong adsorption capacity to host cells. Furthermore, H22Q was present in 10.99% of all EV71 strains in Taiwan, which was significantly more prevalent than that in mainland China and Hong Kong (5.50%), suggesting that the adsorption capacity of some strains in Taiwan to host cells was weak in comparison with that of strains in mainland China.

Studies have shown that the variation A289T in the EV71-VP1 protein is closely related to the occurrence of severe HFMD and that the neurological symptoms caused by EV71 infection are significantly increased when the amino acid at position 289 of VP1 is A (alanine); in contrast, there is low neurotoxicity when the amino acid at position 289 is T (threonine) [36, 38]. In this study, 76.45% (2838 strains) of the virus strains contained an A (alanine), suggesting that most of the EV71 viruses have high neurotoxicity. Moreover, 10.24% (380 strains) of the strains in mainland China (including Hong Kong) and 10.75% (399 strains) of those in Taiwan contained a T (threonine), suggesting low neurotoxicity. Additionally, whether these new mutations will cause the emergence of severe HFMD remains to be further studied, regarding A289V (valine)/D (aspartic acid)/I (isoleucine) mutations.

EV71 can infect human lymphocytes by binding to its receptor molecule, Pselectin glycoprotein ligand-1 (PSGL-1). When the amino acid at position 145, E (glutamic acid), in VP1 is mutated to G (glycine) or Q (glutamine), to the virus binds PSGL-1 more readily, whereas its PSGL-1-binding ability is weakened or lost if position 145 is E (glutamic acid) [39]. In this study, the amino acid at position 145 is E in most strains, and the mutation rate of E145G/Q is 6.63%, suggesting that the emergence of this mutation may be result in a virus that is more likely to infect human lymphocytes.

It has been reported that the E98K mutation may increase the hydrophobicity of VP1, making it easy for large compounds to enter and interfere with VP1 receptor binding, suggesting that E98K mutant viruses are sensitive to larger compounds [40]. Other studies have shown that E145G and N31D mutations are associated with increased virulence of EV71 and may increase the risk of neurological complications, while I262V mutations reduce the risk of neurological complications [41-43]. In this study, the mutation rates of E98K, E145G, N31D and I262V were 6.65%, 3.13%, 7.25% and 2.77%, respectively. These findings indicate that these mutations may play an important role in the pathogenicity of mild and severe EV71-associated HFMD.

Humans are the only natural host and source of EV71, as EV71 cannot infect rodents, which is due mainly to the incompatibility between the virus and rodent cells and the different expression of its scavenger receptor in humans and rodents [44-46]. However, some studies have found that the simultaneous substitution of K98E, E145A and L169F in VP1 of EV71 can cause infection in mice [44]. Our study showed that among 3712 strains, the mutation frequencies of K98E, E145A and L169F were 93.24%, 0.30% and 0.03%, respectively, but no strain with three mutations was found. These findings indicate that humans are still the only host of EV71 in China, but the existence of individual mutations does not rule out the emergence of strains that can infect other mammals after a few years. Therefore, it is important to closely monitor the mutation of the key sites of the EV71-VP1 region.

EV71 is the most important pathogen of children with severe HFMD, which can lead to irreversible sequelae or death of infected children, and it is a serious threat to the health of children [4, 7]. At present, there is no specific drug for the treatment of EV71 infection. The development and marketing of an inactivated EV71 vaccine in China is crucial for the prevention of HFMD caused by EV71 infection [26, 47, 48, 49]^. Phase III clinical trials of the EV71 inactivated vaccine approved in China in 2015 showed that its protective effectiveness against EV71-associated HFMD was more than 90% [47, 50, 51, 52]. However, molecular epidemiological studies of EV71 showed that EV71 gene mutations occur frequently, leading to genetic diversity [28, 29, 30, 31, 53]. These studies imply that there is still a need for strengthening surveillance of EV71 genotypes and the development of new EV71 vaccines.

This study is a retrospective study, and there are some limitations. First, the EV71-VP1 gene sequences from China analyzed in this study were downloaded from the GenBank database but were not tested by us. Due to the limited time, only the VP1 region has been analyzed and studied. In future study, we will conduct genetic research on the complete genome sequence of EV71 in China. Second, the Chinese EV71-VP1 strains registered in GenBank do not cover all provinces of China, and the data in some years are missing, which means that we may have missed some isolates of other genotypes. Third, it is not clear whether some variations in the amino acid sites found in the study are related to the severity of disease or the route of transmission.

In summary, the prevalent strains of EV71 belonged to mainly the C4 genotype; the C4a subgenotype was predominant, the C4b subgenotype was the second most prevalent, and other subgenotypes appeared sporadically in mainland China. The B4 genotype is the major genotype in Taiwan, China, and the epidemic strain is constantly changing. Moreover, the variation in amino acids in the key sites of the EV71-VP1 region is very important for the development of severe HFMD. Taken together, these studies indicated that the genetic characteristics of the EV71-VP1 region should be continuously monitored, which is essential for the prevention and control of EV71-associated HFMD in children and EV71 vaccine design.

Competing interests

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors acknowledge all of the clinical staff throughout China who provided the VP1 protein-encoding region gene sequences and information concerning the EV71 strains used in this study. We gratefully acknowledge American Journal Experts (AJE) (Verification code: 053B-2FE3-F3E3-887C-4651) for providing English language editing services for our manuscript.

Authors’ contributions

Dawei Cui participated in the design of the study. Dawei Cui, Haiyan Sun and Min Gao performed data collection and statistical analysis, Dawei Cui and Haiyan Sun drafted the manuscript. All authors read and approved the final manuscript. We gratefully acknowledge American Journal Experts (AJE) (Verification code: 053B-2FE3-F3E3-887C-4651) for providing English language editing services for our manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81871709), the National Key Programs for Infectious Diseases of China (No. 2017ZX10103008-005), the Natural Science Foundation of Zhejiang Province, China (No. LY16H200001), the Scientific Research Projects of Education of Zhejiang Province, China (No. Y201534117), the Scientific Technology Projects of Health and the Family Planning Commission of Zhejiang Province (No. 2015KYB149).

Availability of data and material

The available data used and/or analyzed during the current study are all included in the manuscript.

Ethics approval and consent to participate

Compliance with ethical standards.

Consent for publication

Not applicable.

Yang F, Ren L, Xiong Z, et al. Enterovirus 71 outbreak in the People's Republic of China in 2008. J CLIN MICROBIOL. 2009;47(7):2351. -2 [PubMed: 19439545].
Wang Y, Feng Z, Yang Y, et al. Hand, foot, and mouth disease in China: patterns of spread and transmissibility. EPIDEMIOLOGY. 2011;22(6):781. – 92 [PubMed: 21968769].
Xing W, Liao Q, Viboud C, et al. Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. LANCET INFECT DIS. 2014;14(4):308–18. [PubMed: 24485991].
Solomon T, Lewthwaite P, Perera D, Cardosa MJ, Mcminn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. LANCET INFECT DIS. 2010;10(11):778. – 90 [PubMed: 20961813].
Luo Z, Su R, Wang W, et al. EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production. PLOS PATHOG. 2019;15(11):e1008142. [PubMed: 31730654].
Antona D, Kossorotoff M, Schuffenecker I, et al. Severe paediatric conditions linked with EV-A71 and EV-D68, France, May to October 2016. Euro Surveill 2016; 21(46).[PubMed: 27918268].
Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. LANCET NEUROL. 2010;9(11):1097. – 105 [PubMed: 20965438].
Kok CC. Therapeutic and prevention strategies against human enterovirus 71 infection. World J Virol. 2015;4(2):78–95. [PubMed: 25964873].
Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341(13):929. – 35 [PubMed: 10498487].
Shih SR, Ho MS, Lin KH, et al. Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in Taiwan, 1998. VIRUS RES. 2000;68(2):127. – 36 [PubMed: 10958984].
Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71. Singapore EMERG INFECT DIS. 2003;9(1):78–85..[PubMed: 12533285].
Herrero LJ, Lee CS, Hurrelbrink RJ, Chua BH, Chua KB, Mcminn PC. Molecular epidemiology of enterovirus 71 in peninsular Malaysia, 1997–2000. ARCH VIROL. 2003;148(7):1369. -85 [PubMed: 12827466].
Guan D, van der Sanden S, Zeng H, et al. Population dynamics and genetic diversity of C4 strains of human enterovirus 71 in Mainland China, 1998–2010. PLOS ONE. 2012;7(9):e44386. [PubMed: 22984501].
Zhu Z, Zhu S, Guo X, et al. Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008. VIROL J 2010; 7: 300.[PubMed: 21050463].
Wang JR, Tuan YC, Tsai HP, Yan JJ, Liu CC, Su IJ. Change of major genotype of enterovirus 71 in outbreaks of hand-foot-and-mouth disease in Taiwan between 1998 and 2000. J CLIN MICROBIOL. 2002;40(1):10. – 5 [PubMed: 11773085].
Yu H, Chen W, Chang H, et al. Genetic analysis of the VP1 region of enterovirus 71 reveals the emergence of genotype A in central China in 2008. VIRUS GENES. 2010;41(1):1. “4 [PubMed: 20306124]. ( : &#8224.
van der Sanden S, van der Avoort H, Lemey P, Uslu G, Koopmans M. Evolutionary trajectory of the VP1 gene of human enterovirus 71 genogroup B and C viruses. J GEN VIROL 2010; 91(Pt 8): 1949-58.[PubMed: 20375223].
Zhang Y, Zhu Z, Yang W, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. VIROL J 2010; 7: 94.[PubMed: 20459851].
Lee KY. Enterovirus 71 infection and neurological complications. Korean J Pediatr. 2016;59(10):395–401. [PubMed: 27826325].
Tan X, Huang X, Zhu S, et al. The persistent circulation of enterovirus 71 in People's Republic of China: causing emerging nationwide epidemics since 2008. PLOS ONE. 2011;6(9):e25662. [PubMed: 21980521].
Tao Z, Wang H, Xu A. Identification of a C2 subgenogroup strain of enterovirus 71 in a retrospective study in Shandong Province, China, from 1990 to 2010. J CLIN MICROBIOL. 2012;50(5):1823. -4 [PubMed: 22357503].
Tao Z, Wang H, Li Y, et al. Molecular epidemiology of human enterovirus associated with aseptic meningitis in Shandong Province, China, 2006–2012. PLOS ONE. 2014;9(2):e89766. [PubMed: 24587020].
Yip CC, Lau SK, Woo PC, Yuen KY. Human enterovirus 71 epidemics: what's next? Emerg Health Threats J 2013; 6: 19780.[PubMed: 24119538].
Chia MY, Chiang PS, Chung WY, Luo ST, Lee MS. Epidemiology of enterovirus 71 infections in Taiwan. PEDIATR NEONATOL. 2014;55(4):243. -9 [PubMed: 24120535].
Huang SW, Cheng HL, Hsieh HY, et al. Mutations in the non-structural protein region contribute to intra-genotypic evolution of enterovirus 71. J BIOMED SCI 2014; 21: 33.[PubMed: 24766641].
Chong P, Liu CC, Chow YH, Chou AH, Klein M. Review of enterovirus 71 vaccines. CLIN INFECT DIS. 2015;60(5):797–803. [PubMed: 25352588].
Chou AH, Liu CC, Chang JY, et al. Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLOS ONE. 2013;8(11):e79783..[PubMed: 24278177].
Bible JM, Iturriza-Gomara M, Megson B, et al. Molecular epidemiology of human enterovirus 71 in the United Kingdom from 1998 to 2006. J CLIN MICROBIOL. 2008;46(10):3192. – 200 [PubMed: 18650362].
Huang SC, Hsu YW, Wang HC, et al. Appearance of intratypic recombination of enterovirus 71 in Taiwan from 2002 to 2005. VIRUS RES. 2008;131(2):250. -9 [PubMed: 18036697].
van der Sanden S, van Eek J, Martin DP, van der Avoort H, Vennema H, Koopmans M. Detection of recombination breakpoints in the genomes of human enterovirus 71 strains isolated in the Netherlands in epidemic and non-epidemic years, 1963–2010. INFECT GENET EVOL. 2011;11(5):886. – 94 [PubMed: 21352955].
Mcwilliam LE, Cabrerizo M, Cardosa J, et al. The association of recombination events in the founding and emergence of subgenogroup evolutionary lineages of human enterovirus 71. J VIROL. 2012;86(5):2676. -85 [PubMed: 22205739].
Xu L, Cui D, Wang L, et al. Genetic characteristics of the P1 coding region of Coxsackievirus A16 associated with hand, foot, and mouth disease in China. MOL BIOL REP. 2018;45(6):1947. “1955 [PubMed: 30182173]. ( : &#8224.
Zhang Y, Tan X, Cui A, et al. Complete genome analysis of the C4 subgenotype strains of enterovirus 71: predominant recombination C4 viruses persistently circulating in China for 14 years. PLOS ONE. 2013;8(2):e56341..[PubMed: 23441179].
Li Y, Zhou Y, Cheng Y, et al. Effectiveness of EV-A71 vaccination in prevention of paediatric hand, foot, and mouth disease associated with EV-A71 virus infection requiring hospitalisation in Henan, China, 2017-18: a test-negative case-control study. Lancet Child Adolesc Health. 2019;3(10):697–704..[PubMed: 31375313].
Weng Y, Chen W, Huang M, He W, Zheng K, Yan Y. Epidemiology and etiology of hand, foot, and mouth disease in Fujian province, 2008–2014. ARCH VIROL. 2017;162(2):535–42..[PubMed: 27796546].
Liu Y, Fu C, Wu S, et al. A novel finding for enterovirus virulence from the capsid protein VP1 of EV71 circulating in mainland China. VIRUS GENES. 2014;48(2):260. – 72 [PubMed: 24442718].
Wu JS, Zhao N, Pan H, et al. Patterns of polymorphism and divergence in the VP1 gene of enterovirus 71 circulating in the Asia-Pacific region between 1994 and 2013. J VIROL METHODS. 2013;193(2):713. – 28 [PubMed: 23933074].
Zhu H, Cao Y, Su W, et al. Enterovirus A71 VP1 Variation A289T Decreases the Central Nervous System Infectivity via Attenuation of Interactions between VP1 and Vimentin In Vitro and In Vivo. Viruses 2019; 11(5).[PubMed: 31121933].
Nishimura Y, Lee H, Hafenstein S, et al. Enterovirus 71 binding to PSGL-1 on leukocytes: VP1-145 acts as a molecular switch to control receptor interaction. PLOS PATHOG. 2013;9(7):e1003511. [PubMed: 23935488].
Chen TC, Liu SC, Huang PN, Chang HY, Chern JH, Shih SR. Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants. J BIOMED SCI. 2008;15(3):291–300. [PubMed: 18196474].
Le TV, Nguyen V, Nguyen QH, Pham DT. Molecular epidemiology analysis of enterovirus 71 strains isolated in Dak Lak, Vietnam, 2011–2016. J MED VIROL. 2019;91(1):56–64. [PubMed: 30132913].
Zhang B, Wu X, Huang K, et al. The variations of VP1 protein might be associated with nervous system symptoms caused by enterovirus 71 infection. BMC INFECT DIS 2014; 14: 243.[PubMed: 24886383].
Kobayashi K, Sudaka Y, Takashino A, Imura A, Fujii K, Koike S. Amino Acid Variation at VP1-145 of Enterovirus 71 Determines Attachment Receptor Usage and Neurovirulence in Human Scavenger Receptor B2 Transgenic Mice. J VIROL 2018; 92(15).[PubMed: 29848584].
Victorio CB, Xu Y, Ng Q, Meng T, Chow VT, Chua KB. Cooperative effect of the VP1 amino acids 98E, 145A and 169F in the productive infection of mouse cell lines by enterovirus 71 (BS strain). Emerg Microbes Infect 2016; 5: e60.[PubMed: 27329847].
Yang CH, Liang CT, Jiang ST, et al. A Novel Murine Model Expressing a Chimeric mSCARB2/hSCARB2 Receptor Is Highly Susceptible to Oral Infection with Clinical Isolates of Enterovirus 71. J VIROL 2019; 93(11).[PubMed: 30894476].
Zhang H, Song Z, Zou J, et al. An infectious clone of enterovirus 71(EV71) that is capable of infecting neonatal immune competent mice without adaptive mutations. Emerg Microbes Infect. 2020;9(1):427–38..[PubMed: 32079505].
Zhu FC, Meng FY, Li JX, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. LANCET 2013; 381(9882): 2024-32.[PubMed: 23726161].
Mao QY, Wang Y, Bian L, Xu M, Liang Z. EV71 vaccine, a new tool to control outbreaks of hand, foot and mouth disease (HFMD). EXPERT REV VACCINES. 2016;15(5):599–606. [PubMed: 26732723].
Yang B, Liu F, Liao Q, et al. Epidemiology of hand, foot and mouth disease in China, 2008 to 2015 prior to the introduction of EV-A71 vaccine. Euro Surveill 2017; 22(50).[PubMed: 29258646].
Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014; 370(9): 829 – 37.[PubMed: 24571755].
Zhu F, Xu W, Xia J, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med. 2014;370(9):818. – 28 [PubMed: 24571754].
Hu YM, Wang X, Wang JZ, et al. Immunogenicity, safety, and lot consistency of a novel inactivated enterovirus 71 vaccine in Chinese children aged 6 to 59 months. CLIN VACCINE IMMUNOL. 2013;20(12):1805. -11 [PubMed: 24108780].
Bessaud M, Razafindratsimandresy R, Nougairede A, et al. Molecular comparison and evolutionary analyses of VP1 nucleotide sequences of new African human enterovirus 71 isolates reveal a wide genetic diversity. PLOS ONE. 2014;9(3):e. 90624 [PubMed: 24598878].

Download PDF

Journal Publication

published 14 Aug, 2020

Read the published version in Gut Pathogens →

Editorial decision: Major revision
18 Jul, 2020
Editor assigned by journal
16 Jul, 2020
Submission checks completed at journal
15 Jul, 2020
Editor invited by journal
15 Jul, 2020

You are reading this older preprint version

Read the latest preprint version →

Molecular characteristics of VP1 region of enterovirus 71 strains in China

Status:

Journal Publication

Version 2

Abstract

Figures

Introduction

Methods

2. Results

3. Discussion

4. Conclusion

Declarations

References

Status:

Journal Publication

Version 2