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
Overview
Affiliations
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.
An efficient complementation system for replication of defective poliovirus mutants.
Arita M J Virol. 2024; 98(7):e0052324.
PMID: 38837378 PMC: 11265389. DOI: 10.1128/jvi.00523-24.
Yan J, Wang M, Li X, Fan J, Yu R, Kang M Microbiol Spectr. 2024; 12(4):e0333223.
PMID: 38441464 PMC: 10986554. DOI: 10.1128/spectrum.03332-23.
Weng K, Tee H, Tseligka E, Cagno V, Mathez G, Rosset S Cell Rep. 2023; 42(4):112389.
PMID: 37058406 PMC: 10590055. DOI: 10.1016/j.celrep.2023.112389.
Murine models of neonatal susceptibility to a clinical strain of enterovirus A71.
Xie J, Hu X, Li H, Zhu H, Lin W, Li L Virus Res. 2023; 324:199038.
PMID: 36599394 PMC: 10194309. DOI: 10.1016/j.virusres.2022.199038.
Cheng D, Chiu Y, Huang S, Lien Y, Chang C, Tsai H Viruses. 2022; 14(10).
PMID: 36298861 PMC: 9608817. DOI: 10.3390/v14102306.