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Updated: Mar 11, 2026
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
Clinically isolated enterovirus A71 subgenogroup C4 strain with lethal pathogenicity in 14-day-old mice and the
Yi Xu1, Shuzhi Ma2, Limeng Zhu3
1Guangzhou Women and Children's Medical Center, Guangzhou Medical University Guangzhou, China.
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.
Insights
A new mouse model using Enterovirus A71 (EV-A71) subgenogroup C4 strain GZ-CII effectively mimics human neurological symptoms. This model aids in evaluating vaccines and therapeutics for EV-A71, a cause of hand, foot, and mouth disease.
Area of Science:
- Virology
- Immunology
- Neurology
Background:
- Enterovirus A71 (EV-A71) subgenogroup C4 causes hand, foot, and mouth disease (HFMD) and severe neurological complications in children.
- Current vaccine and antiviral development is limited by the absence of animal models that replicate human EV-A71 neurological symptoms.
Purpose of the Study:
- To establish and validate a mouse model for studying EV-A71 subgenogroup C4 pathogenesis and for evaluating potential vaccines and therapeutics.
- To identify genetic factors contributing to EV-A71 virulence in the established mouse model.
Main Methods:
- Isolation of a highly virulent EV-A71 subgenogroup C4 strain (GZ-CII) from pediatric HFMD patients.
- Intraperitoneal inoculation of GZ-CII into young mice to assess disease progression and neurological manifestations.
- Administration of an inactivated EV-A71 vaccine and anti-EV-A71 immune serum to evaluate protective efficacy.
- Genomic sequencing of GZ-CII and comparison with an avirulent strain, followed by site-directed mutagenesis (VP2-K149I) to assess virulence contribution.
Main Results:
- Intraperitoneal infection with EV-A71 GZ-CII induced progressive neurological disease in mice up to 14 days old.
- Vaccination and passive immunization with anti-EV-A71 serum conferred protection against GZ-CII infection in mice.
- Genomic analysis revealed unique mutations in GZ-CII, with the VP2-K149I mutation significantly enhancing viral replication and virulence in mice.
- The VP2-K149I mutation was identified as a key factor in the increased virulence of EV-A71 subgenogroup C4 in the mouse model.
Conclusions:
- The EV-A71 GZ-CII mouse model successfully recapitulates key neurological aspects of human EV-A71 infection.
- This validated mouse model is suitable for the preclinical evaluation of vaccine candidates and antiviral therapies targeting EV-A71 subgenogroup C4.
- The VP2-K149I mutation is crucial for the enhanced virulence of EV-A71 subgenogroup C4 in this murine model, providing insights into viral pathogenesis.
