Molecular Basis for a Lack of Correlation between Viral Fitness and Cell Killing Capacity

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Abstract
The relationship between parasite fitness and virulence has been the object of experimental and theoretical studies often with conflicting conclusions. Here, we provide direct experimental evidence that viral fitness and virulence, both measured in the same biological environment provided by host cells in culture, can be two unrelated traits. A biological clone of foot-and-mouth disease virus acquired high fitness and virulence (cell killing capacity) upon large population passages in cell culture. However, subsequent plaque-to-plaque transfers resulted in profound fitness loss, but only a minimal decrease of virulence. While fitness-decreasing mutations have been mapped throughout the genome, virulence determinants—studied here with mutant and chimeric viruses—were multigenic, but concentrated on some genomic regions. Therefore, we propose a model in which viral virulence is more robust to mutation than viral fitness. As a consequence, depending on the passage regime, viral fitness and virulence can follow different evolutionary trajectories. This lack of correlation is relevant to current models of attenuation and virulence in that virus de-adaptation need not entail a decrease of virulence. Virulence expresses the harm that parasites inflict upon their hosts. Many studies have addressed the basis of virulence and its effect on host and parasite survival. It has generally been accepted that one of the components of parasite virulence is fitness, or the capacity of the parasite to multiply in its host. Some models have equated virulence with fitness. In the present study, we use foot-and-mouth disease virus (FMDV) to document that virulence and fitness—measured in the same biological environment provided by cells in culture—can be unrelated traits. This has been achieved by multiplying the virus in a manner that mutations accumulated in its genome. Mutations decreased fitness dramatically, but not virulence. Chimeric and mutant viruses were constructed to show that virulence is influenced by only some of the FMDV genes, while fitness is influenced by the entire genome. For this reason, virulence is more robust (“resistant”) than fitness to the effects of deleterious mutations. The fact that virulence can be unrelated to fitness has implications for the design of anti-viral vaccines because it suggests that it may be possible to design high fitness, low virulence strains to stimulate the host immune response. Furthermore, in modelling studies it cannot be assumed that virulence is equal to fitness.