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Published on: April 28, 2019
A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection
Ya-Fang Wang1, Chun-Ting Chou, Huan-Yao Lei
1Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
Abstract:
A mouse-adapted enterovirus 71 (EV71) strain with increased virulence in mice, MP4, was generated after four serial passages of the parental EV71 strain 4643 in mice. Strain MP4 exhibited a larger plaque size, grew more rapidly, and was more cytotoxic in vitro than strain 4643. Although strains 4643 and MP4 both induced apoptosis of SK-N-SH human neuroblastoma cells, MP4 was more virulent than 4643 in 1-day-old mice (50% lethal doses, 10(2) and 10(4) PFU/mouse, respectively). Strain MP4 (5 x 10(6) PFU/mouse), but not 4643, could orally infect 7-day-old mice, resulting in rear-limb paralysis followed by death 5 to 9 days after inoculation with the virus. Histopathologically, neuronal loss and apoptosis were evident in the spinal cords as well as the brain stems of the infected mice. The limb muscles displayed massive necrosis. There was early and transient virus replication in the intestines, whereas the spinal cord, brain, and muscle became the sites of viral replication during the late phase of the infection. Virus transmission occurred among infected and noninfected cagemates, as demonstrated by the occurrence of seroconversion and the presence of viable viruses in the stool samples of the latter. Protection against EV71 challenge was demonstrated following administration of hyperimmune serum 1 day after inoculation with the virus. Nucleotide sequence analysis of the genome of EV71 strain MP4 revealed four nucleotide changes on the 5' untranslated region, three on the VP2 region, and eight on the 2C region, resulting in one and four amino acid substitutions in the VP2 and 2C proteins, respectively.
Insights
A mouse-adapted enterovirus 71 (EV71) strain, MP4, shows increased virulence and causes paralysis and death in young mice. This adapted strain replicates in the central nervous system and muscles, and can transmit between mice.
Area of Science:
- Virology
- Pathogenesis
- Molecular Biology
Background:
- Enterovirus 71 (EV71) is a significant human pathogen causing neurological diseases.
- Understanding EV71 virulence factors is crucial for developing effective countermeasures.
- Mouse models are essential for studying EV71 pathogenesis and testing interventions.
Purpose of the Study:
- To generate and characterize a mouse-adapted EV71 strain with enhanced virulence.
- To investigate the pathogenesis and transmission of the adapted strain in a murine model.
- To identify genetic changes associated with increased virulence.
Main Methods:
- Serial passage of EV71 strain 4643 in mice to generate a virulent strain (MP4).
- In vitro characterization of plaque size, growth kinetics, and cytotoxicity.
- In vivo virulence studies in neonatal mice, including LD50 determination and histopathological analysis.
- Viral replication site determination and transmission studies.
- Genomic and amino acid sequence analysis of EV71 strains.
Main Results:
- The mouse-adapted EV71 strain MP4 exhibited increased virulence, larger plaque size, faster growth, and higher cytotoxicity compared to the parental strain.
- MP4 caused paralysis and death in 7-day-old mice upon oral inoculation, with significant neuronal apoptosis and muscle necrosis.
- Viral replication was observed in the intestines, central nervous system, and muscles, with evidence of transmission between cagemates.
- Genetic analysis revealed specific nucleotide and amino acid changes in the MP4 strain, particularly in the 5' untranslated region, VP2, and 2C regions.
Conclusions:
- The mouse-adapted EV71 strain MP4 provides a valuable model for studying EV71 pathogenesis, particularly neurotropism and transmission.
- Specific genetic alterations in MP4 contribute to its enhanced virulence and distinct pathological features.
- Further research into these genetic changes could inform the development of antiviral strategies and vaccines against EV71.
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