The emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016

Emerging Microbes & Infections, Jul 2018

Jiayu Wang, Zheng Teng, Wei Chu, Fanghao Fang, Xiaoqing Cui, Xiaokui Guo, Xi Zhang, Bruce R. Thorley, Yongzhang Zhu

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The emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016

Wang et al. Emerging Microbes & Infections The emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016 Jiayu Wang 0 Zheng Teng 0 Wei Chu 1 Fanghao Fang 0 Xiaoqing Cui 0 Xiaokui Guo 2 Xi Zhang 0 Bruce R. Thorley 3 Yongzhang Zhu 4 0 Microbiology Laboratory, Shanghai Municipal Center for Disease Control and Prevention , Shanghai , China 1 Microbiology Laboratory, Huangpu Center for Disease Control and Prevention , Shanghai , China 2 Department of Microbiology and Immunology, Institutes of Medical Science, Shanghai Jiao Tong University School of Medicine , Shanghai , China 3 National Enterovirus Reference Laboratory, WHO Polio Regional Reference Laboratory, Victorian Infectious Diseases Reference Laboratory, Doherty Institute , Melbourne, VIC 3000 , Australia 4 Department of Clinical Microbiology, Institute of Antibiotics, Huashan Hospital, Fudan University , Shanghai , China Dear Editors, We report the first outbreak and spread of one Coxsackievirus A16 (CV-A16) novel Genogroup D recombinant strain in Shanghai, China, in 2016, 2 years after an initial report in France1. CV-A16 belongs to the Enterovirus (EV) A species and is one of the major serotypes that causes hand, foot, and mouth disease (HFMD). CV-A16 can be classified into three genogroups, A-C, based on the VP4 and VP1 gene sequences2-5. Genogroup B can be further divided into B1 (B1a-B1c) and B26. CV-A16 Genogroup D is a novel recombinant genogroup. The epidemiological origin can be traced to Peru7. Hassel et al. reported its first emergence and circulation in France during 2010-20141 and provided further detailed evidence of an intertype recombinant origin of CV-A16 genogroup D. To the best of our knowledge, no more report of the novel genogroup D could be found in the PubMed database. The genogroup D Shanghai strain, designated SH-HP16-51, was isolated from a mild HFMD case collected by our laboratory surveillance system on 5 October 2016. The patient was a 3-year-old girl. The epidemiological origin was traced to an aggregated case of 14 suspected HFMD patients reported in Pudong CDC. Between 2 and 5 October, 11 and 3 students among these 14 patients belonged to two adjacent classes in one kindergarten, - respectively. The first case occurred on 2 October with fever (high temperature 38.9 ?C), sore throat, and oral ulcers, and the child was diagnosed with HFMD on the next day. Unfortunately, clinical samples of only two patients were successfully collected in this outbreak because the kindergarten was quickly closed before we could collect other patient samples. However, no EV RNA was detected in the first case sample. In addition, although the guardians of both the first and second cases denied any history of contact with foreigners or travel abroad 2 weeks before the onset, we cannot exclude the possibility that the SH-HP-16-51 strain originated from other geographic locations, like France, because of increasingly frequent international business and communication. The EV genome of strain SH-HP-16-51 was detected in a throat swab after RNA extraction. Pan EV and CV-A16 were confirmed with a commercial real-time RT-PCR Kit (BioPerfectus Technologies, Jiangsu, China). A human rhabdomyosarcoma cell line was then used for virus isolation. When typical cytopathic effects occurred (data not shown), culture medium and cells were harvested for purification. The complete genome was determined as described1,8 and submitted to GenBank (accession number: MG948605). The SH-HP-16-51 genome was 7231 bp long. Phylogenetic trees were constructed by using nucleotide sequences of the VP1, P1, P2, and P3 regions of the reference strains representing all genogroups with complete genome sequences. Phylogenetic analyses based on the complete VP1 sequence (891 bp) provided evidence that the isolate SH-HP-16-51 belonged to CV-A16 genogroup D and was most closely related to the strains isolated from France and Peru (Fig. 1a). These strains constituted a lineage distinct from other CV-A16 subgenogroups and were placed into the same clade D when constructing phylogenetic trees using the P1, P2, and P3 genome regions (Figure S1). Furthermore, phylogenetic analysis based on VP2?VP4, 2A?2C, 3A?3D gene sequences also showed similar results (data not shown). Nucleotide sequence identities between different CV-A16 genogroups and an outgroup (enterovirus 71 prototype) were compared (Table S1). Sequences of the capsid region (P1) of the SH-HP-16-51 strain showed 93.74?98.87% nt identity with the genogroup D strains reported in France, suggesting that the Shanghai strain belonged to the same genogroup. In nonstructural regions (P2 and P3), the Shanghai strain also had the highest sequence identity with the genogroup D strains, showing 90.88?98.44% and 90.41?98.89% nt identity, respectively. Comparative analysis of the ORF sequences also showed similar amino acid changes to those reported1 (data not shown) between clades B and D. Hence, the high nt identity between the SH-HP-16-51 strain and the French effective protection against recombinant genogroup D or the onset of herpangina. Further studies emphasize the need for improving novel recombinant CV-A16 genogroup D surveillance. Genetic and antigenic characterization studies will no doubt assist in efforts to prevent and control potential transmission and epidemics. Acknowledgements This study was supported by the Fourth 3-year Action Plan for Public Health of the Shanghai Municipal Commission of Health and Family Planning (GWTD2015S01 and 15GWZK0101) and the Project of Health and Family Planning Commission of the Huangpu area, Shanghai (2012-HGG-53). 1. Hassel , C. et al. Phylogeography of coxsackievirus A16 reveals global transmission pathways and recent emergence and spread of a recombinant genogroup . J. Virol . 91 , https://doi.org/10.1128/JVI.00630- 17 ( 2017 ). 2. Iwai , M. et al. Genetic changes of coxsackievirus A16 and enterovirus 71 isolated from hand, foot, and mouth disease patients in Toyama, Japan between 1981 and 2007 . Jpn. J. Infect. Dis . 62 , 254 - 259 ( 2009 ). 3. Li , L. et al. Genetic characteristics of human enterovirus 71 and coxsackievirus A16 circulating from 1999 to 2004 in Shenzhen, People's Republic of China . J. Clin. Microbiol . 43 , 3835 - 3839 ( 2005 ). 4. Perera , D. et al. Molecular phylogeny of modern coxsackievirus A16 . Arch. Virol . 152 , 1201 - 1208 ( 2007 ). 5. Nix , W. A. , Oberste , M. S. & Pallansch , M. A. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens . J. Clin. Microbiol . 44 , 2698 - 2704 ( 2006 ). 6. Zhang, Y. et al. Molecular evidence of persistent epidemic and evolution of subgenotype B1 coxsackievirus A16-associated hand, foot, and mouth disease in China . J. Clin. Microbiol . 48 , 619 - 622 ( 2010 ). 7. Carrion , G. et al. Molecular epidemiology of coxsackievirus A16 strains from four sentinel surveillance sites in Peru . Int. J. Infect. Dis . 52 , 83 - 85 ( 2016 ). 8. Chen , L. et al. Complete genome sequence of a coxsackievirus a16 strain, isolated from a fatal case in shenzhen, southern china , in 2014. Genome Announc . 3 , https://doi.org/10.1128/genomeA. 00391 - 15 ( 2015 ). 9. Wang , J. et al. Epidemiological and serological surveillance of hand-foot-andmouth disease in Shanghai , China, 2012 - 2016 . Emerg. Microbes Infect. 7 , 8 ( 2018 ). 10. Yip , C. C. et al. Emergence of enterovirus 71 ?double-recombinant? strains belonging to a novel genotype D originating from southern China: first evidence for combination of intratypic and intertypic recombination events in EV71 . Arch. Virol. 155 , 1413 - 1424 ( 2010 ). 11. Yip , C. C. et al. Genetic characterization of EV71 isolates from 2004 to 2010 reveals predominance and persistent circulation of the newly proposed genotype D and recent emergence of a distinct lineage of subgenotype C2 in Hong Kong . Virol. J. 10 , 222 ( 2013 ).


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Jiayu Wang, Zheng Teng, Wei Chu, Fanghao Fang, Xiaoqing Cui, Xiaokui Guo, Xi Zhang, Bruce R. Thorley, Yongzhang Zhu. The emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016, Emerging Microbes & Infections, 2018, DOI: 10.1038/s41426-018-0134-x