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

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Published inJournal of Virology Vol. 78; no. 15; pp. 7916 - 7924
Main Authors WANG, Ya-Fang, CHOU, Chun-Ting, YU, Chun-Keung, LEI, Huan-Yao, LIU, Ching-Chuan, WANG, Shih-Min, YAN, Jing-Jou, SU, Ih-Jen, WANG, Jen-Reng, YEH, Trai-Ming, CHEN, Shun-Hua
Format Journal Article
LanguageEnglish
Published Washington, DC American Society for Microbiology 01.08.2004
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Abstract Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue JVI About JVI Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy JVI RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0022-538X Online ISSN: 1098-5514 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to JVI .asm.org, visit: JVI       
AbstractList 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 × 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.
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.
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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 × 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.
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 super(2) and 10 super(4) PFU/mouse, respectively). Strain MP4 (5 x 10 super(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.
Author Shih-Min Wang
Shun-Hua Chen
Ya-Fang Wang
Ching-Chuan Liu
Ih-Jen Su
Chun-Keung Yu
Chun-Ting Chou
Trai-Ming Yeh
Jing-Jou Yan
Huan-Yao Lei
Jen-Reng Wang
AuthorAffiliation 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 China 6
AuthorAffiliation_xml – name: 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 China 6
Author_xml – sequence: 1
  givenname: Ya-Fang
  surname: WANG
  fullname: WANG, Ya-Fang
  organization: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 2
  givenname: Chun-Ting
  surname: CHOU
  fullname: CHOU, Chun-Ting
  organization: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 3
  givenname: Chun-Keung
  surname: YU
  fullname: YU, Chun-Keung
  organization: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 4
  givenname: Huan-Yao
  surname: LEI
  fullname: LEI, Huan-Yao
  organization: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 5
  givenname: Ching-Chuan
  surname: LIU
  fullname: LIU, Ching-Chuan
  organization: Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 6
  givenname: Shih-Min
  surname: WANG
  fullname: WANG, Shih-Min
  organization: Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 7
  givenname: Jing-Jou
  surname: YAN
  fullname: YAN, Jing-Jou
  organization: Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 8
  givenname: Ih-Jen
  surname: SU
  fullname: SU, Ih-Jen
  organization: Department of Clinical Medicine, Collegeof Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 9
  givenname: Jen-Reng
  surname: WANG
  fullname: WANG, Jen-Reng
  organization: Department of Medical Technology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 10
  givenname: Trai-Ming
  surname: YEH
  fullname: YEH, Trai-Ming
  organization: Department of Medical Technology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
– sequence: 11
  givenname: Shun-Hua
  surname: CHEN
  fullname: CHEN, Shun-Hua
  organization: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Province of China
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10.1056/NEJM199909233411301
10.1007/BF02253368
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Issue 15
Keywords Picornaviridae
Motor system disorder
Size
Virulence
Central nervous system
Enterovirus
Neuroblastoma
Limb
Paralysis
Neurological disorder
Dose
Human
Nervous system diseases
Digestive system
Rodentia
Oral administration
Malignant tumor
In vitro
Strain
Virus
Infection
Vertebrata
Mammalia
Mouse
Cell death
Animal
Oral cavity disease
Autonomic neuropathy
Apoptosis
Language English
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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@mail.ncku.edu.tw.
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Snippet Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley...
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...
ABSTRACT A mouse-adapted enterovirus 71 (EV71) strain with increased virulence in mice, MP4, was generated after four serial passages of the parental EV71...
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SubjectTerms 5' Untranslated Regions - chemistry
Animals
Antibodies, Viral - immunology
Apoptosis
Biological and medical sciences
Central Nervous System Diseases - etiology
Central Nervous System Diseases - pathology
Enterovirus - pathogenicity
Enterovirus 71
Enterovirus Infections - pathology
Enterovirus Infections - virology
Fundamental and applied biological sciences. Psychology
Humans
Medical sciences
Mice
Mice, Inbred ICR
Microbiology
Miscellaneous
Pathogenesis and Immunity
Tumors
Virology
Virulence
Virus Replication
Title A Mouse-Adapted Enterovirus 71 Strain Causes Neurological Disease in Mice after Oral Infection
URI http://jvi.asm.org/content/78/15/7916.abstract
https://www.ncbi.nlm.nih.gov/pubmed/15254164
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