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      Access to a main alphaherpesvirus receptor, located basolaterally in the respiratory epithelium, is masked by intercellular junctions

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          Abstract

          The respiratory epithelium of humans and animals is frequently exposed to alphaherpesviruses, originating from either external exposure or reactivation from latency. To date, the polarity of alphaherpesvirus infection in the respiratory epithelium and the role of respiratory epithelial integrity herein has not been studied. Equine herpesvirus type 1 (EHV1), a well-known member of the alphaherpesvirus family, was used to infect equine respiratory mucosal explants and primary equine respiratory epithelial cells (EREC), grown at the air-liquid interface. EHV1 binding to and infection of mucosal explants was greatly enhanced upon destruction of the respiratory epithelium integrity with EGTA or N-acetylcysteine. EHV1 preferentially bound to and entered EREC at basolateral cell surfaces. Restriction of infection via apical inoculation was overcome by disruption of intercellular junctions. Finally, basolateral but not apical EHV1 infection of EREC was dependent on cellular N-linked glycans. Overall, our findings demonstrate that integrity of the respiratory epithelium is crucial in the host’s innate defence against primary alphaherpesvirus infections. In addition, by targeting a basolaterally located receptor in the respiratory epithelium, alphaherpesviruses have generated a strategy to efficiently escape from host defence mechanisms during reactivation from latency.

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          Most cited references68

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          Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling

          The epithelial cadherin (E-cadherin)–catenin complex binds to cytoskeletal components and regulatory and signaling molecules to form a mature adherens junction (AJ). This dynamic structure physically connects neighboring epithelial cells, couples intercellular adhesive contacts to the cytoskeleton, and helps define each cell’s apical–basal axis. Together these activities coordinate the form, polarity, and function of all cells in an epithelium. Several molecules regulate AJ formation and integrity, including Rho family GTPases and Par polarity proteins. However, only recently, with the development of live-cell imaging, has the extent to which E-cadherin is actively turned over at junctions begun to be appreciated. This turnover contributes to junction formation and to the maintenance of epithelial integrity during tissue homeostasis and remodeling.
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            Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical- basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein

            Tight junctions, the most apical of the intercellular junctions that connect individual cells in a epithelial sheet, are thought to form a seal that restricts paracellular and intramembrane diffusion. To analyze the functioning of tight junctions, we generated stable MDCK strain 2 cell lines expressing either full-length or COOH-terminally truncated chicken occludin, the only known transmembrane component of tight junctions. Confocal immunofluorescence and immunoelectron microscopy demonstrated that mutant occludin was incorporated into tight junctions but, in contrast to full-length chicken occludin, exhibited a discontinuous junctional staining pattern and also disrupted the continuous junctional ring formed by endogenous occludin. This rearrangement of occludin was not paralleled by apparent changes in the junctional morphology as seen by thin section electron microscopy nor apparent discontinuities of the junctional strands observed by freeze-fracture. Nevertheless, expression of both wild-type and mutant occludin induced increased transepithelial electrical resistance (TER). In contrast to TER, particularly the expression of COOH-terminally truncated occludin led to a severalfold increase in paracellular flux of small molecular weight tracers. Since the selectivity for size or different types of cations was unchanged, expression of wild-type and mutant occludin appears to have activated an existing mechanism that allows selective paracellular flux in the presence of electrically sealed tight junctions. Occludin is also involved in the formation of the apical/basolateral intramembrane diffusion barrier, since expression of the COOH-terminally truncated occludin was found to render MDCK cells incapable of maintaining a fluorescent lipid in a specifically labeled cell surface domain.
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              Herpesviruses: latency and reactivation – viral strategies and host response

              Eight members of the Herpesviridae family commonly infect humans, and close to 100% of the adult population is infected with at least one of these. The five that cause the most health concerns are: herpes simplex virus (HSV) type 1 and 2, Epstein–Barr virus (EBV), cytomegalovirus (CMV), and varicella zoster virus (VZV). In addition, there are human herpes virus (HHV) types 6–8. The review starts by introducing possible viral strategies in general. The particular biology and host relationship of the various human herpesviruses, including their pathology, are examined subsequently. Factors that contribute to the maintenance of latency and reactivation of viral replication are discussed. There will be special reference to how these viruses exploit and contribute to pathology in the oral cavity. Reactivation does not necessarily imply clinical symptoms, as reflected in the asymptomatic shedding of EBV and CMV from oral mucosa. The immune response and the level of viral output are both important to the consequences experienced.
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                Author and article information

                Contributors
                hans.nauwynck@ugent.be
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                30 November 2017
                30 November 2017
                2017
                : 7
                : 16656
                Affiliations
                [1 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Department of Virology, Parasitology and Immunology, , Faculty of Veterinary Medicine, Ghent University, ; Salisburylaan 133, 9820 Merelbeke, Belgium
                [2 ]ISNI 0000 0001 2097 5006, GRID grid.16750.35, Department of Molecular Biology and Princeton Neuroscience Institute, , Princeton University, ; 119 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544 USA
                [3 ]ISNI 0000 0001 2150 1785, GRID grid.17088.36, Department of Pathobiology and Diagnostic Investigation, , College of Veterinary Medicine, Michigan State University, ; 784 Wilson Road, East Lansing, Michigan 48824 USA
                [4 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Department of Morphology, , Faculty of Veterinary Medicine, Ghent University, ; Salisburylaan 133, 9820 Merelbeke, Belgium
                Author information
                http://orcid.org/0000-0003-1598-3057
                Article
                16804
                10.1038/s41598-017-16804-5
                5709510
                29192251
                baf5d59b-d2c9-44c3-8087-b568ad7085b8
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 September 2017
                : 16 November 2017
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