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Title: Early events in the pathogenesis of foot-and-mouth disease in pigs; identification of oropharyngeal tonsils as sites of primary and sustained viral replication

Author
item STENFELDT, CAROLINA - 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: 8/2/2014
Publication Date: 9/3/2014
Citation: Stenfeldt, C., Pacheco Tobin, J., Rodriguez, L.L., Arzt, J. 2014. Early events in the pathogenesis of foot-and-mouth disease in pigs; identification of oropharyngeal tonsils as sites of primary and sustained viral replication. PLoS One. DOI:10.1371/journal.pone.0106859.

Interpretive Summary: Foot-and-mouth disease (FMD) continues to be the most important transboundary disease of livestock. Yet, lack of understanding of basic aspects of the disease prevent progress in vaccine development. In pigs, it is unknown how FMD virus (FMDV) establishes infection and gets shed into the environment. In the current work, an experimental study was performed with the objective of elucidating the early events of FMDV infection in pigs. After inoculation, the virus was first detected in tonsils of the oropharynx at 6 hours after inoculation. Shedding of FMDV in oral secretions increased markedly by 12 hours after inoculation; virus was detected in the blood by 18-24 hours after infection, with characteristic lesions appearing at 48 hours after infection. Throughout the infection, viral proteins were microscopically detected within the oropharyngeal tonsils which has never been demonstrated previously. It is concluded that the oropharyngeal tonsils are the first site of FMDV infection in the pig, and that these tonsils continue to support replication of virus through the infectious period, contributing to shedding of large amounts of virus into the environment.

Technical Abstract: A time-course study was performed to elucidate the early events of foot-and-mouth disease virus (FMDV) infection in pigs subsequent to simulated natural inoculation. The earliest detectable event was primary infection in the lingual and paraepiglotic tonsils at 6 hours post inoculation (hpi) characterized by regional localization of viral RNA, viral antigen, and infectious virus. At this time FMDV antigen was localized by immuno-microscopy to crypt epithelium of the paraepiglottic tonsils, with detection in cytokeratin-positive epithelial cells and CD172a-expressing leukocytes. De novo replication of FMDV was first detected in swab samples at 12hpi and viremia occurred at 18-24 hpi, approximately 24 hours prior to the appearance of vesicular lesions. From 12 through 78 hpi, microscopic detection of FMDV was consistently localized to cytokeratin-positive cells within morphologically characteristic segments of oropharyngeal tonsil crypt epithelium. During this period, leukocyte populations expressing CD172a, SLA-DQ class II and/or CD8 were found in close proximity to infected epithelial cells, but with little or no co-localization with viral proteins. Similarly, M-cells expressing cytokeratin-18 did not co-localize with FMDV proteins. Intra-epithelial micro-vesicles composed of acantholytic epithelial cells expressing large amounts of structural and non-structural FMDV proteins were present within crypts of the tonsil of the soft palate during peak clinical infection. Overall, it is concluded that primary FMDV replication in pigs occurs in the paraepiglottic tonsils. Furthermore, oropharyngeal tonsils continue to support substantial FMDV replication during viremia and peak clinical infection, contributing to shedding of large amounts of virus into the environment.