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Journal of Virology, August 2004, p. 7916-7924, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.7916-7924.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Mouse-Adapted Enterovirus 71 Strain Causes Neurological Disease in Mice after Oral Infection

Ya-Fang Wang,1 Chun-Ting Chou,2 Huan-Yao Lei,2 Ching-Chuan Liu,3 Shih-Min Wang,3 Jing-Jou Yan,4 Ih-Jen Su,5 Jen-Reng Wang,6 Trai-Ming Yeh,6 Shun-Hua Chen,2 and Chun-Keung Yu2*

Institute of Basic Medical Sciences,1 Departments of Microbiology and Immunology,2 Pediatrics,3 Pathology,4 Clinical Medicine,5 Medical Technology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China6

Received 16 January 2004/ Accepted 19 April 2004

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, 102 and 104 PFU/mouse, respectively). Strain MP4 (5 x 106 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.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China. Phone: 886-6-2353535, ext. 5673. Fax: 886-6-2082705. E-mail: dckyu{at}mail.ncku.edu.tw.

Journal of Virology, August 2004, p. 7916-7924, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.7916-7924.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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