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Title: Pathogenesis of primary foot-and-mouth disease virus infection in the nasopharynx of vaccinated and non-vaccinated cattle

Author
item STENFELDT, CAROLINA - Oak Ridge Institute For Science And Education (ORISE)
item ESCHBAUMER, MICHAEL - Oak Ridge Institute For Science And Education (ORISE)
item REKANT, STEVEN - Oak Ridge Institute For Science And Education (ORISE)
item Pacheco Tobin, Juan
item Rodriguez, Luis
item Arzt, Jonathan

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/11/2015
Publication Date: 11/23/2015
Citation: Stenfeldt, C., Eschbaumer, M., Rekant, S.I., Pacheco Tobin, J., Rodriguez, L.L., Arzt, J. 2015. Pathogenesis of primary foot-and-mouth disease virus infection in the nasopharynx of vaccinated and non-vaccinated cattle. PLoS One. 10(11): e0143666. doi: 10.1371/journal.pone.0143666.

Interpretive Summary: Foot-and-mouth disease (FMD) is one of the greatest threats to livestock in the United States. Control of recent FMD outbreaks in the UK and South Korea involved slaughter of millions of animals, resulting in public outcry. Current control plans in the U.S. emphasize the intention to use vaccination if an outbreak occurs.However, much remains unknown about the basic mechanisms of protection and infection in vaccinated animals. In this study, important events of foot-and-mouth disease virus (FMDV) infection in vaccinated and non-vaccinated cattle were compared through experimental infections. In non-vaccinated animals, FMDV was detected in the upper respiratory-tract during early during infection and the virus spread rapidly through blood and tissues, inducing severe disease signs. In contrast, vaccinated steers were protected against internal spread of the virus and external signs of disease. However, the virus infected the same sites in the upper respiratory tract as in non-vaccinated animals, causing a localized, silent infection. FMDV distribution and host immune responses in tissues were further characterized microscopically. These analyses demonstrated a more rapid activation of immune response to infection in the vaccinated animals; specifically, close interactions between virus-infected cells and specific cells of the immune system were observed. This is the first study to ever characterize mechanisms of FMDV-host interactions in vaccinated animals. The evidence derived from this study will help inform vaccine development and FMD control program implementation.

Technical Abstract: A time-course pathogenesis study was performed to compare and contrast primary foot-and-mouth disease virus (FMDV) infection in vaccinated and non-vaccinated cattle following simulated-natural virus exposure. FMDV genome and infectious virus were detected during the initial phase of infection from both categories of animals with consistent predilection for the nasopharyngeal mucosa. A rapid progression of infection occurred in non-vaccinated animals with viremia and wide-spread dissemination of virus whilst steers immunized with a recombinant, adenovirus-vectored, FMDV vaccine were protected from generalized FMD. Analysis of micro-anatomic distribution of virus in tissues by lasercapture microdissection localized primary FMDV infection to the follicle associated epithelium of nasopharyngeal mucosa in both groups of animals, with concurrent detection of viral RNA in nasopharyngeal MALT follicles only in vaccinated steers. FMDV structural and non-structural proteins were detected in epithelial cells of nasopharyngeal mucosa by immuno-microscopy at 24 hours after inoculation in both non-vaccinated and vaccinated steers. Co-localization of CD11c+/MHC II+ cells with viral protein occurred at primary infection sites in vaccinated steers whilst similar host-virus interactions were only observed at later time points, in association with viremia and clinical disease, in non-vaccinated steers. Additionally, substantial populations of CD8+/CD3- host cells, representing presumptive NK-cells, were observed in association with foci of primary FMDV infection in vaccinated steers whilst absent in non-vaccinated steers. Although vaccination protected cattle from clinical FMD, the virus infected epithelial cells of the nasopharyngeal mucosa, causing a localized subclinical infection that enables shedding and potential persistence of infectious virus. Additionally, these findings suggest a marked difference in the immediate host response to infection between non-vaccinated and vaccinated animals with a rapid induction of anti-viral responses at primary infection sites of vaccinated cattle.