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Caracterización y bases moleculares de la persistencia y la virulencia del virus de la fiebre aftosa en cultivos celulares

AuthorsHerrera, Mónica
AdvisorDomingo, Esteban ; Escarmis Homs, Cristina
KeywordsVirus de la fiebre aftosa
Issue Date2006
PublisherUniversidad Autónoma de Madrid
AbstractRNA viruses are the most abundant viruses in nature. Their adaptation is based on the continuous generation of mutant genomes, resulting in extremely heterogeneous and dynamic mutant swarms, termed viral quasispecies. We have used foot-and-mouth disease virus (FMDV) as a model to study the structure, dynamics and adaptive potential of viral quasispecies. The picornavirus FMDV usually causes an acute, systemic infection in vivo, and cytophatic infection in cell culture. The virus can, however, persist asymptomatically in the epithelium of the soft palate and oropharynx of rumiants. In the 1980’s our laboratory established and characterized a BHK-21 cell line persistently infected with FMDV. In this Doctoral Thesis we have re-examined persistence of FMDV in BHK-21 cells by establishing again two parallel lineages of persistent cultures, beginning with the same stocks of cells and the same clone of FMDV. We report that the pattern of coevolution of cells and virus was very similar to that described previously. Relative quantitation of both positive and negative FMDV RNA strands has revealed an imbalance in the proportion of positive versus negative strand RNA in the persistently infected cells, that is a property of the virus with some participation of the cells, and which could contribute to the molecular mechanism of persistence. We also describe the behavior of a FMDV clone (H5 95) which has a history of repeated serial plaque-to-plaque transfers in BHK-21 cells, that attained a very low fitness value relative to its parental reference virus (C-S8c1), and yet, its virulence for BHK-21 cells was significantly higher than that of its parental clone. A comparative study of the capacity to kill BHK-21 cells of chimeric FMDVs constructed with cDNA copies of the two parental FMDVs (H5 95 y C-S8c1) and mutant FMDVs C-S8c1 containing the mutations found in gene 2C of H5 95, indicates that the enhanced virulence for BHK-21 cells of the low fitness clone is a polygenic trait, and that non-structural protein 2C is a virulence determinant for FMDV. We provide direct evidence that viral fitness and capacity to kill cells can be either linked or unrelated traits, and that such disparate relationship depends on the evolutionary history of the virus. This has a number of implications for viral pathogenesis, and the existence of specific mutations that affect differentially fitness and virulence opens the way to engineer candidate attenuated vaccine strains unable to kill the host while maintaining replicative competence.
DescriptionTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular, Fecha de lectura noviembre 2006
Appears in Collections:(CBM) Tesis
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