Tesis doctoral de Marta Sanz-ramos Rojo
Rna virus populations are complex and dynamic distributions of closely related but non-identical genomes termed quasispecies. The types of mutants in a distribution and the interactions among them determine the quasispecies properties as a whole and their survival capacity as a unit of selection. The large heterogeneity in quasispecies, which increases the adaptive potential of viral populations to different environments, is due to the low fidelity of viral rna polymerases and the lack of error-repair activities during viral replication. Alterations in the resulting high mutation frequency compromises viral survival and adaptation to different selective pressures. There is a new antiviral strategy named lethal mutagenesis based in increasing the mutation frequency to levels incompatible with the viability of viral populations, achieved by replication in the presence of mutagens. the main aim of this ph.D. Thesis is to study the biological implications of quasispecies properties in infections in vivo, using a mouse model for foot-and-mouth disease virus (fmdv) infections. Fmdv causes a lethal systemic infection in c57bl/6 mice, showing high viral loads in pancreas. Viral populations isolated from pancreas after one passage in mice presented an attenuated phenotype for mice, with no lethality even at the highest dose tested. By contrast, virus from serum of the same mice displayed a similar virulence to that of the parental wild-type clone, and virus isolated from spleen exhibited an intermediate phenotype. However, viral populations from pancreas, spleen and serum showed indistinguishable consensus genomic nucleotide sequences and average mutant spectrum complexities. We propose a model for these differences in virulence for mice based on the proportion of ¿pathogenic¿ and ¿nonpathogenic¿ genomes within the quasispecies, and on the molecular interactions between them, without a readily detectable manifestation in the consensus genomic sequence or in the mutant spectrum complexity. in addition, we describe that an increase in the mutant spectrum complexity, by treatment with the mutagenic agent ribavirin, leads to an attenuation of fmdv populations in mice. Interestingly, the mutagenized viral population contained biological clones which displayed higher virulence for mice than the assembled quasispecies, suggesting that these genomes of higher virulence were suppressed by the surrounding mutant spectrum.
Datos académicos de la tesis doctoral «Dinámica de cuasiespecies del virus de la fiebre aftosa in vivo.«
- Título de la tesis: Dinámica de cuasiespecies del virus de la fiebre aftosa in vivo.
- Autor: Marta Sanz-ramos Rojo
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 21/07/2009
Dirección y tribunal
- Director de la tesis
- Mauricio Garcia Mateu
- Tribunal
- Presidente del tribunal: albert Bosch navarro
- Antonio Mas lópez (vocal)
- Ana Grande perez (vocal)
- José María Almemdral del rio (vocal)