Summary auto-generated
This study examined the secondary structure of the 3'-untranslated region (3'-UTR) of yellow fever virus (YFV) to understand how it relates to viral virulence and attenuation. Researchers used genetic algorithm-based RNA secondary structure prediction combined with comparative sequence analysis of 21 YFV strains (14 wild and 7 vaccine) to model the folding of the distal 380 nucleotides of the 3'-UTR. They identified several conserved structural elements containing compensatory mutations, indicating functional importance. Critically, they discovered structural polymorphisms that strongly correlated with virulence: all wild-type pathogenic strains exhibited one characteristic folding pattern, while attenuated vaccine strains showed a different pattern caused by specific point mutations. The vaccine strain 17DD displayed an intermediate structure combining features of both wild-type and vaccine-type folding and exhibited intermediate virulence in mouse models. These findings suggest that secondary structure of the 3'-UTR, independent of coding region mutations, influences YFV pathogenicity and may enable new vaccine development strategies based on rational modification of this non-coding region.
Key findings
- Wild-type pathogenic YFV strains fold the 3'-UTR region III into a long stable structure, while vaccine strains carry a point mutation that disrupts this structure and prevents wild-type folding
- All vaccine strains share common nucleotide substitutions in the 3'-UTR leading to similar conformational changes, despite being derived from two different parental wild-type strains
- The 17DD vaccine strain retains wild-type folding in region I while adopting vaccine-type folding in region III, and displays intermediate virulence compared to other vaccine strains
- Strong association exists between predicted secondary structure of the 3'-UTR and viral virulence, suggesting this non-coding region plays a functional role in pathogenicity
- Rational modification of 3'-UTR secondary structure could enable development of vaccines with high immunogenicity and reduced virulence without altering viral proteins
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Abstract
A genetic algorithm-based RNA secondary structure prediction was combined with comparative sequence analysis to construct models of folding for the distal 380 nucleotides of the 3'-untranslated region (3'-UTR) of yellow fever virus (YFV). A number of structural elements that are thermodynamically stable, conserved in shape, and confirmed by compensatory mutations were revealed. At the same time structural polymorphisms were observed among strains of YFV. These polymorphisms showed an association with virulence: all wild and pathogenic strains were likely to be folded in a significantly different way from vaccine strains with reduced virulence. Structural divergence was also found among vaccine strains, with 17DD, the most virulent in the mouse model, exhibiting an intermediate pattern of folding, combining structural features of both wild and vaccine strains. The observation of a strong association between secondary structure of the 3'-UTR and virulence of YFV may help elucidate the molecular mechanisms of virus attenuation and lead to new strategies of vaccine development directed towards rational modification of secondary structure of the 3'-UTR.