title: Clinically isolated enterovirus A71 subgenogroup C4 strain with lethal pathogenicity in 14-day-old mice and the application as an EV-A71 mouse infection model.
abstract: The Enterovirus A71 (EV-A71) subgenogroup C4 is prevalent in China. EV-A71 causes hand, foot and mouth disease (HFMD) in children and may lead to severe neurological diseases. The development of antiviral and protective vaccines against EV-A71 is significantly hindered by the lack of suitable animal models to recapitulate human neurological symptoms. In this study, GZ-CII, a highly virulent EV-A71 subgenogroup C4 strain, was isolated from hospitalized children with HFMD. Intraperitoneal infections of GZ-CII resulted in progressive neurological disease in mice as old as 14 days. Administration of an inactivated EV-A71 vaccine or an anti-EV-A71 immune serum protected the mice against the GZ-CII infection. This demonstrated that a mouse model with EV-A71 GZ-CII could be used to evaluate potential vaccine candidates and therapeutics for subgenogroup C4. Comparing the genome sequence of GZ-CII with that of the avirulent EV-A71 subgenogroup C4 strain revealed unique mutations in GZ-CII. When mutation VP2-K149I was introduced into the nonpathogenic EV-A71 subgenogroup C4 strain, the variant similar to GZ-CII significantly increased viral replication and virulence in mice. These results indicated that the VP2-K149I mutation played an important role in enhancing the virulence of the EV-A71 subgenogroup C4 strain in mice, and that mice infected with the GZ-CII strain are a promising model for evaluating vaccines and therapeutics against the EV-A71 subgenogroup C4.
authors.affiliation: Guangzhou Women and Children's Medical Center, Guangzhou Medical University Guangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China; Sino-French Hoffmann Institute of Immunology, State Key Laboratory of Respiratory Disease, College of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Ma
authors.affiliation: Sino-French Hoffmann Institute of Immunology, State Key Laboratory of Respiratory Disease, College of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
authors.forename: Limeng
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China.
authors.forename: Zhiqiu
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China; Sino-French Hoffmann Institute of Immunology, State Key Laboratory of Respiratory Disease, College of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Yin
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China; Sino-French Hoffmann Institute of Immunology, State Key Laboratory of Respiratory Disease, College of Basic Medical Science, Guangzhou Medical University, Guangzhou, China. Electronic address: peng_tao@gibh.ac.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: Guangdong South China United Vaccine Institute, Guangzhou, China; The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China. Electronic address: wang_yi79@hotmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000367:Age Factors; D000818:Animals; D002648:Child; D002681:China; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000276:immunology / Q000517:prevention & control / Q000628:therapy / Q000821:virology*; D006232:Hand, Foot and Mouth Disease / Q000276:immunology / Q000517:prevention & control / Q000628:therapy / Q000821:virology*; D006801:Humans; D007116:Immunization, Passive; D051379:Mice; D009154:Mutation; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology; D014774:Virulence; D014779:Virus Replication
chemical_list: D015164:Vaccines, Inactivated; D014765:Viral Vaccines
keywords: Enterovirus A71 (EV-A71); Mouse infection model; Primary isolate; Vaccine