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Its genetic characterization and pathogenic properties are largely unknown. Here, we report 39 circulating CV-A6 strains isolated in 2013 from HFMD patients in northeast China. Three major clusters of CV-A6 were identified and related to CV-A6, mostly from Shanghai, indicating that domestic CV-A6 strains were responsible for HFMD emerging in northeast China. Four full-length CV-A6 genomes representing each cluster were sequenced and analyzed further. Bootscanning tests indicated that all four CV-A6-Changchun strains were most likely recombinants between the CV-A6 prototype Gdula and prototype CV-A4 or CV-A4-related viruses, while the recombination pattern was related to, yet distinct from, the strains isolated from other regions of China. Furthermore, different CV-A6 strains showed different capabilities of viral replication, release, and pathogenesis in a mouse model. Further analyses indicated that viral protein 2C contributed to the diverse pathogenic abilities of CV-A6 by causing autophagy and inducing cell death. To our knowledge, this study is the first to report lethal and nonlethal strains of CV-A6 associated with HFMD. The 2C protein region may play a key role in the pathogenicity of CV-A6 strains.<\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Hand, foot, and mouth disease (HFMD) is a major and persistent threat to infants and children. Besides the most common pathogens, such as enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16), other enteroviruses are increasingly contributing to HFMD. The present study focused on the recently emerged CV-A6 strain. We found that CV-A6 strains isolated in Changchun City in northeast China were associated with domestic origins. These Changchun viruses were novel recombinants of the CV-A6 prototype Gdula and CV-A4. Our results imply that measures to control CV-A6 transmission are urgently needed. Further analyses revealed differing pathogenicities in strains isolated in a neonatal mouse model. One of the possible causes has been narrowed down to the viral protein 2C, using phylogenetic studies, viral sequences, and direct tests on cultured human cells. Thus, the viral 2C protein is a promising target for antiviral drugs to prevent CV-A6-induced tissue damage.\n          <\/jats:p>","DOI":"10.1128\/jvi.00303-18","type":"journal-article","created":{"date-parts":[[2018,3,22]],"date-time":"2018-03-22T09:38:20Z","timestamp":1521711500000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":34,"title":["Divergent Pathogenic Properties of Circulating Coxsackievirus A6 Associated with Emerging Hand, Foot, and Mouth Disease"],"prefix":"10.1128","volume":"92","author":[{"given":"Shao-Hua","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"},{"name":"Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Wang","sequence":"additional","affiliation":[{"name":"Jilin Provincial Center for Disease Control and Prevention, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan-Pan","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Xu","sequence":"additional","affiliation":[{"name":"Jilin Provincial Center for Disease Control and Prevention, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guan-Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bai-Song","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Huan","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Fang","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China"},{"name":"Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"R81","article-title":"Epidemiological, virological, and clinical features of an epidemic of hand, foot, and mouth disease in England and Wales","volume":"6","author":"Bendig JW","year":"1996","unstructured":"Bendig JW, Fleming DM. 1996. 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