|STENFELDT, CAROLINA - Oak Ridge Institute For Science And Education (ORISE)|
|ESCHBAUMER, MICHAEL - Oak Ridge Institute For Science And Education (ORISE)|
|REKANT, STEVEN - Oak Ridge Institute For Science And Education (ORISE)|
|PACHECO, JUAN - Oak Ridge Institute For Science And Education (ORISE)|
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/21/2016
Publication Date: 5/4/2016
Citation: Stenfeldt, C., Eschbaumer, M., Rekant, S.I., Pacheco, J.M., Smoliga, G.R., Hartwig, E.J., Rodriguez, L.L., Arzt, J. 2016. The foot-and-mouth disease carrier state divergence in cattle. Journal of Virology. doi: 10.1128/JVL00388-16.
Interpretive Summary: Foot-and-mouth disease virus (FMDV) is a highly contagious virus that can cause two forms of disease in cattle: the typical acute severe form or the silent, persistent, infection. Regardless of whether animals are vaccinated and thereby protected against symptoms of disease, the virus can establish a persistent infection in the upper respiratory tract. This publication describes the results of a series of experimental studies in which vaccinated and non-vaccinated cattle were infected with FMDV and monitored through 35 days after infection (dpi). Persistent FMDV infection was detected in approximately 65% of infected animals, regardless of vaccination status. By monitoring the dynamics of virus shedding from infected animals, it was concluded that within the group of animals that successfully cleared the infection, shedding of virus ceased by 21 dpi in non-vaccinated cattle and 10 dpi in vaccinated cattle. Thus, there was a clear time point of divergence by which it was possible to tell if an animal had developed persistent infection or not. Microscopic analyses of tissue samples localized the persistent virus to specific regions of the upper respiratory tract (nasopharynx). Quantification of viral loads as well as expression of different factors of the host immune response suggested that presence of virus in tissues was associated with a inhibition of the local anti-viral immune response.
Technical Abstract: The pathogenesis of persistent foot-and-mouth disease virus (FMDV) infection was investigated following simulated-natural virus exposure of 43 cattle that were either naïve or vaccinated using a recombinant, adenovirus-vectored vaccine. Although vaccinated cattle were protected against clinical disease, the prevalence of FMDV persistence was similar in nonvaccinated and vaccinated cattle. Detailed monitoring of antemortem infection dynamics demonstrated that the subclinical divergence that dictates whether an animal develops persistent FMDV infection or not occurred at 21 days post infection (dpi) in nonvaccinated cattle, and at 10 dpi in vaccinated animals. Time-course, post-mortem investigations in non-vaccinated cattle confirmed that infectious virus was cleared from peripheral sites by 10 dpi, while selectively persisting within the nasopharynx of a subset of animals. Contrastingly, anatomic distribution of virus in vaccinated, clinically protected cattle was restricted to the pharynx throughout both early and persistent phases of infection. Investigations by immunomicroscopy localized FMDV structural and non-structural protein to lymphoid follicle associated epithelium of the dorsal soft palate and dorsal nasopharynx in persistently infected cattle. Parallel analyses based on lasercapture micro dissection (LCM) confirmed a wider micro-anatomic distribution of viral RNA including both non-lymphoid and lymphoid epithelium, as well as subepithelial lymphoid follicles. Host transcriptome analysis of tissue samples processed by LCM provided evidence of suppression of antiviral host factors within micro-anatomic compartments containing FMDV RNA. This work provides novel insights in the intricate mechanisms of FMDV persistence and contributes to further understanding of this critical aspect of FMDV pathogenesis.