Abstract
Foot-and-mouth disease virus (FMDV) infects hosts as a population of closely related viruses referred to as a quasispecies. The behavior of this quasispecies has not been described in detail in natural host species. In this study, virus samples collected from vaccinated and non-vaccinated cattle up to 35 days post-experimental infection with FMDV A24-Cruzeiro were analyzed by deep-sequencing. Vaccination induced significant differences compared to viruses from non-vaccinated cattle in substitution rates, entropy, and evidence for adaptation. Genomic variation detected during early infection reflected the diversity inherited from the source virus (inoculum), whereas by 12 days post infection, dominant viruses were defined by newly acquired mutations. Mutations conferring recognized fitness gain occurred and were associated with selective sweeps. Persistent infections always included multiple FMDV subpopulations, suggesting distinct foci of infection within the nasopharyngeal mucosa. Subclinical infection in vaccinated cattle included very early bottlenecks associated with reduced diversity within virus populations. Viruses from both animal cohorts contained putative antigenic escape mutations. However, these mutations occurred during later stages of infection, at which time transmission is less likely to occur. This study improves upon previously published work by analyzing deep sequences of samples, allowing for detailed characterization of FMDV populations over time within multiple hosts.
Highlights
Foot-and-mouth disease (FMD) is a viral disease affecting even-toed ungulates, causing economically devastating effects on animal production and international trade [1,2,3]
Among the 10 cattle followed through study-end, seven were determined to be persistently infected with foot-and-mouth disease virus (FMDV), while three individuals fully cleared infection during the transitional phase of infection
FMDV genomic change detected during early infection was consistent with neutral evolution in all cattle
Summary
Foot-and-mouth disease (FMD) is a viral disease affecting even-toed ungulates, causing economically devastating effects on animal production and international trade [1,2,3]. The economic impacts associated with decreased production, disease surveillance, trade restrictions, and vaccination campaigns comprise a large burden to FMD-endemic and neighboring countries [3]. The etiologic agent of FMD, foot-and-mouth disease virus (FMDV) (family: Picornaviridae, genus: Aphthovirus) is a single-stranded positive-sense RNA virus with a high mutation rate [6]. Often associated with positive selection and antigenic escape, are commonly detected in the capsid protein coding regions [8,9,10]. The GH loop in capsid protein VP1 is important for host cell entry and antibody-mediated neutralization [11]. The Arg-Gly-Asp (RGD) motif within this GH loop interacts directly with the host cell integrin receptors (e.g., αvβ6) (reviewed in [12])
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