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      The Pathogenesis of Foot-and-Mouth Disease in Pigs

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          Abstract

          The greatest proportion of foot-and-mouth disease (FMD) clinical research has been dedicated to elucidating pathogenesis and enhancing vaccine protection in cattle with less efforts invested in studies specific to pigs. However, accumulated evidence from FMD outbreaks and experimental investigations suggest that critical components of FMD pathogenesis, immunology, and vaccinology cannot be extrapolated from investigations performed in cattle to explain or to predict outcomes of infection or vaccination in pigs. Furthermore, it has been shown that failure to account for these differences may have substantial consequences when FMD outbreaks occur in areas with dense pig populations. Recent experimental studies have confirmed some aspects of conventional wisdom by demonstrating that pigs are more susceptible to FMD virus (FMDV) infection via exposure of the upper gastrointestinal tract (oropharynx) than through inhalation of virus. The infection spreads rapidly within groups of pigs that are housed together, although efficiency of transmission may vary depending on virus strain and exposure intensity. Multiple investigations have demonstrated that physical separation of pigs is sufficient to prevent virus transmission under experimental conditions. Detailed pathogenesis studies have recently demonstrated that specialized epithelium within porcine oropharyngeal tonsils constitute the primary infection sites following simulated natural virus exposure. Furthermore, epithelium of the tonsil of the soft palate supports substantial virus replication during the clinical phase of infection, thus providing large amounts of virus that can be shed into the environment. Due to massive amplification and shedding of virus, acutely infected pigs constitute a considerable source of contagion. FMDV infection results in modulation of several components of the host immune response. The infection is ultimately cleared in association with a strong humoral response and, in contrast to ruminants, there is no subclinical persistence of FMDV in pigs. The aim of this review is to provide an overview of knowledge gained from experimental investigations of FMD pathogenesis, transmission, and host response in pigs. Details of the temporo-anatomic progression of infection are discussed in relation to specific pathogenesis events and the likelihood of transmission. Additionally, relevant aspects of the host immune response are discussed within contexts of conventional and novel intervention strategies of vaccination and immunomodulation.

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          IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors.

          The interferon-regulatory factor (IRF) family of transcription factors was initially found to be involved in the induction of genes that encode type I interferons. IRFs have now been shown to have functionally diverse roles in the regulation of the immune system. Recently, the crucial involvement of IRFs in innate and adaptive immune responses has been gaining much attention, particularly with the discovery of their role in immunoregulation by Toll-like receptors and other pattern-recognition receptors.
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            Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.

            The pleiotropic activities of interferons (IFNs) are mediated primarily through the transcriptional regulation of many downstream effector genes. The mRNA profiles from IFN-alpha, -beta, or -gamma treatments of the human fibrosarcoma cell line, HT1080, were determined by using oligonucleotide arrays with probe sets corresponding to more than 6,800 human genes. Among these were transcripts for known IFN-stimulated genes (ISGs), the expression of which were consistent with previous studies in which the particular ISG was characterized as responsive to either Type I (alpha, beta) or Type II (gamma) IFNs, or both. Importantly, many novel IFN-stimulated genes were identified that were diverse in their known biological functions. For instance, several novel ISGs were identified that are implicated in apoptosis (including RAP46/Bag-1, phospholipid scramblase, and hypoxia inducible factor-1alpha). Furthermore, several IFN-repressed genes also were identified. These results demonstrate the usefulness of oligonucleotide arrays in monitoring mammalian gene expression on a broad and unprecedented scale. In particular, these findings provide insights into the basic mechanisms of IFN actions and ultimately may contribute to better therapeutic uses for IFNs.
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              Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules.

              We have identified a type II Ca2+-dependent lectin displaying mannose-binding specificity, exclusively expressed by Langerhans cells (LC), and named Langerin. LC are uniquely characterized by Birbeck granules (BG), which are organelles consisting of superimposed and zippered membranes. Here, we have shown that Langerin is constitutively associated with BG and that antibody to Langerin is internalized into these structures. Remarkably, transfection of Langerin cDNA into fibroblasts created a compact network of membrane structures with typical features of BG. Langerin is thus a potent inducer of membrane superimposition and zippering leading to BG formation. Our data suggest that induction of BG is a consequence of the antigen-capture function of Langerin, allowing routing into these organelles and providing access to a nonclassical antigen-processing pathway.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/298200
                URI : http://frontiersin.org/people/u/339324
                URI : http://frontiersin.org/people/u/348023
                URI : http://frontiersin.org/people/u/339120
                Journal
                Front Vet Sci
                Front Vet Sci
                Front. Vet. Sci.
                Frontiers in Veterinary Science
                Frontiers Media S.A.
                2297-1769
                23 May 2016
                2016
                : 3
                : 41
                Affiliations
                [1] 1Agricultural Research Service (ARS), Foreign Animal Disease Research Unit (FADRU), Plum Island Animal Disease Center (PIADC), United States Department of Agriculture (USDA) , Greenport, NY, USA
                [2] 2PIADC Research Participation Program, Oak Ridge Institute for Science and Education , Oak Ridge, TN, USA
                [3] 3Department of Pathobiology and Veterinary Science, CANR, University of Connecticut , Storrs, CT, USA
                Author notes

                Edited by: Preben William Willeberg, Technical University of Denmark, Denmark

                Reviewed by: Hsin-Yi Weng, Purdue University, USA; Gustavo Machado, World Health Organization/Pan American Health Organization, USA

                *Correspondence: Jonathan Arzt, jonathan.arzt@ 123456ars.usda.gov

                Specialty section: This article was submitted to Veterinary Epidemiology and Economics, a section of the journal Frontiers in Veterinary Science

                Article
                10.3389/fvets.2016.00041
                4876306
                27243028
                d621ede3-aa7e-4944-980c-34ebfa920076
                Copyright © 2016 Stenfeldt, Diaz-San Segundo, de los Santos, Rodriguez and Arzt.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 March 2016
                : 06 May 2016
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 97, Pages: 12, Words: 9506
                Funding
                Funded by: U.S. Department of Agriculture 10.13039/100000199
                Award ID: ARS-CRIS Project 1940-32000-057-00D
                Funded by: Science and Technology Directorate 10.13039/100008287
                Award ID: HSHQPM-13-X-00131, HSHQPM-13-X-00113
                Funded by: University of Connecticut 10.13039/100007710
                Award ID: Specific Cooperative Agreement #58-1940-4-003
                Categories
                Veterinary Science
                Review

                foot-and-mouth disease,foot-and-mouth disease virus,pigs,pathogenesis,host response,virus diseases,virology

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