Genome analysis of enterovirus 71 strains differing in mouse pathogenicity.

Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD) and is occasionally associated with severe neurological diseases. The investigation of virulence determinants of EV71 is rudimentary. Therefore, it is important to understand the relationship between EV71 virulence and genomic information. In this study, a series of analyses about full-length genomic sequence were performed on six EV71 strains isolated from HFMD patients with either severe or mild clinical symptoms. A one-day-old BALB/c mouse model was used to study the infection characteristics. Results showed all six strains were of the subgenogroup C4a. Viral full-length genomic sequence analysis showed that a total of 40 nucleotide differences between strains of highly and low virulence were revealed. Among all mutations, three nucleotide mutations were found in the untranslated region. A mutation, nt115, at internal ribozyme entry site (IRES) caused RNA secondary structural change. The other 37 mutations were all located in the open reading frame resulting in 8 amino acid mutations. Importantly, we discovered that a mutation of amino acid (Asn1617 → Asp1617) in the 3C proteinase (3C(pro)) of highly and low pathogenic strains could lead to conformational change at the active center, suggesting that this site may be a virulence determinant of EV71.