Cooperative effect of the attenuation determinants derived from poliovirus sabin 1 strain is essential for attenuation of enterovirus 71 in the NOD/SCID mouse infection model.
Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and is also associated with serious neurological disorders. An attenuated EV71 strain [EV71(S1-3')] has been established in the cynomolgus monkey infection model; this strain contains the attenuation determinants derived from the type 1 poliovirus vaccine strain, Sabin 1 [PV1(Sabin)], in the 5' nontranslated region (NTR), 3D polymerase, and 3' NTR. In this study, we analyzed the effect of the attenuation determinants of PV1(Sabin) on EV71 infection in a NOD/SCID mouse infection model. We isolated a mouse-adapted EV71 strain [EV71(NOD/SCID)] that causes paralysis of the hind limbs in 3- to 4-week-old NOD/SCID mice by adaptation of the virulent EV71(Nagoya) strain in the brains of NOD/SCID mice. A single mutation at nucleotide 2876 that caused an amino acid change in capsid protein VP1 (change of the glycine at position 145 to glutamic acid) was essential for the mouse-adapted phenotype in NOD/SCID mice. Next, we introduced attenuation determinants derived from PV1(Sabin) along with the mouse adaptation mutation into the EV71(Nagoya) genome. In 4-week-old mice, the determinants in the 3D polymerase and 3' NTR, which are the major temperature-sensitive determinants, had a strong effect on attenuation. In contrast, the effect of individual determinants was weak in 3-week-old NOD/SCID mice, and all the determinants were required for substantial attenuation. These results suggest that a cooperative effect of the attenuation determinants of PV1(Sabin) is essential for attenuated neurovirulence of EV71.
Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan. minetaro@nih.go.jp
Minetaro
M
Arita
Yasushi
Y
Ami
Takaji
T
Wakita
Hiroyuki
H
Shimizu
D019943:Amino Acid Substitution; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004770:Enterovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000473:pathology / Q000517:prevention & control*; D006321:Heart / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000473:pathology / Q000821:virology; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D017955:Poliovirus; D011055:Poliovirus Vaccine, Oral / Q000235:genetics* / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D014771:Virion / Q000235:genetics / Q000276:immunology; D014774:Virulence / Q000235:genetics
D036022:Capsid Proteins; D011055:Poliovirus Vaccine, Oral; D014613:Vaccines, Attenuated