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Attenuation of Mengo virus through genetic engineering of the 5' noncoding poly(C) tract
G M Duke1, J E Osorio, A C Palmenberg
1Institute for Molecular Virology, University of Wisconsin, Madison 53706.
Abstract:
The murine cardioviruses, such as the Mengo and encephalomyocarditis viruses, and the bovine aphthoviruses, such as foot-and-mouth disease virus, are distinguished among positive-strand RNA viruses by the presence of long homopolymeric poly(C) tracts within their 5' noncoding sequences. Although the specific lengths (60-350 bases) and sequence discontinuities (for example, uridine residues) that sometimes disrupt the homopolymer have served to characterize natural viral isolates, the biological function of the poly(C) region has never been clear. We now report that complementary DNA-mediated truncation of the Mengo virus poly(C) tract dramatically attenuates the pathogenicity of the virus in mice. Animals injected with viruses with short tracts not only survived inoculation of up to 50 micrograms live virus (10(11) plaque-forming units) but consistently produced high titres of neutralizing antibodies, which conferred long-term immunogenic protection from (normally) lethal virus challenge. We propose that analogous synthetic strains of foot and mouth disease virus could serve as the basis for new attenuated vaccines.
Insights
Truncating the poly(C) tract in Mengo virus significantly reduced its pathogenicity in mice. This modification led to virus survival and robust antibody production, suggesting potential for new vaccines.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Positive-strand RNA viruses, including cardioviruses and aphthoviruses, possess unique 5' noncoding poly(C) tracts.
- The biological significance of these poly(C) tracts in viral pathogenesis has remained largely undetermined.
Purpose of the Study:
- To investigate the functional role of the poly(C) tract in the 5' noncoding sequence of Mengo virus.
- To explore the potential of modifying poly(C) tracts for vaccine development.
Main Methods:
- Complementary DNA-mediated truncation of the Mengo virus poly(C) tract.
- In vivo pathogenicity studies in mice.
- Assessment of neutralizing antibody titers and long-term immunogenic protection.
Main Results:
- Truncation of the poly(C) tract dramatically attenuated Mengo virus pathogenicity in mice.
- Mice infected with truncated virus survived high doses and developed significant neutralizing antibodies.
- This immune response conferred long-term protection against lethal virus challenge.
Conclusions:
- The poly(C) tract is critical for Mengo virus pathogenicity.
- Modified aphthoviruses, like foot-and-mouth disease virus, with truncated poly(C) tracts could serve as novel attenuated vaccines.
- This research opens avenues for developing safer and more effective viral vaccines.