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.

Abstract

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.

• Authors: Minetaro Arita, Yasushi Ami, Takaji Wakita, Hiroyuki Shimizu
• Journal: Journal of virology (J Virol) Vol. 82 Issue 4 Pg. 1787-97 (Feb 2008) ISSN: 1098-5514 [Electronic] United States
• PMID: 18057246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Capsid Proteins
• Poliovirus Vaccine, Oral
• Vaccines, Attenuated

Topics

• Amino Acid Substitution
• Animals
• Capsid Proteins (genetics, immunology)
• Disease Models, Animal
• Enterovirus (genetics, immunology, pathogenicity)
• Enterovirus Infections (pathology, prevention & control)
• Heart (virology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Muscle, Skeletal (pathology, virology)
• Mutation
• Myocardium (pathology)
• Poliovirus
• Poliovirus Vaccine, Oral (genetics, immunology)
• Vaccines, Attenuated (genetics, immunology, therapeutic use)
• Virion (genetics, immunology)
• Virulence (genetics)