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      Synergistic Viral Replication of Marek’s Disease Virus and Avian Leukosis Virus Subgroup J is Responsible for the Enhanced Pathogenicity in the Superinfection of Chickens

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          Abstract

          Superinfection of Marek’s disease virus (MDV) and avian leukosis virus subgroup J (ALV-J) causes lethal neoplasia and death in chickens. However, whether there is synergism between the two viruses in viral replication and pathogenicity has remained elusive. In this study, we found that the superinfection of MDV and ALV-J increased the viral replication of the two viruses in RNA and protein level, and synergistically promoted the expression of IL-10, IL-6, and TGF-β in chicken embryo fibroblasts (CEF). Moreover, MDV and ALV-J protein expression in dual-infected cells detected by confocal laser scanning microscope appeared earlier in the cytoplasm and the nucleus, and caused more severe cytopathy than single infection, suggesting that synergistically increased MDV and ALV-J viral-protein biosynthesis is responsible for the severe cytopathy. In vivo, compared to the single virus infected chickens, the mortality and tumor formation rates increased significantly in MDV and ALV-J dual-infected chickens. Viral loads of MDV and ALV-J in tissues of dual-infected chickens were significantly higher than those of single-infected chickens. Histopathology observation showed that more severe inflammation and tumor cells metastases were present in dual-infected chickens. In the present study, we concluded that synergistic viral replication of MDV and ALV-J is responsible for the enhanced pathogenicity in superinfection of chickens.

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          Most cited references38

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          Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function.

          The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.
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            Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens

            Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population. Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts.
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              Quantitative methods for assessing drug synergism.

              Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and many other diseases and situations. The determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug's potencies. The basis of that demonstration is the concept of dose equivalence, which is discussed here and applied to an experimental design and data analysis known as isobolographic analysis. That method, and a related method of analysis that also uses dose equivalence, are presented in this brief review, which provides the mathematical basis for assessing synergy and an optimization strategy for determining the dose combination.
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                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                18 May 2018
                May 2018
                : 10
                : 5
                : 271
                Affiliations
                [1 ]College of Veterinary Medicine, Shandong Agricultural University, Tai’an 271018, China; tiramisurd@ 123456163.com (J.Z.); 13515381026@ 123456163.com (G.-L.Z.); m15253197976@ 123456163.com (X.-M.W.); duxusheng12345@ 123456163.com (X.-S.D.); ssu6307@ 123456163.com (S.S.); chgli1981@ 123456126.com (C.-G.L.)
                [2 ]Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Tai’an 271018, China
                [3 ]The Pirbright Institute & UK-China Centre of Excellence on Avian Disease Research, Pirbright, Ash Road, Guildford, Surrey GU24 0NF, UK; venugopal.nair@ 123456pirbright.ac.uk (V.N.); yongxiu.yao@ 123456pirbright.ac.uk (Y.-X.Y.)
                Author notes
                [* ]Correspondence: honey@ 123456sdau.edu.cn ; Tel.: +86-13505484575
                [†]

                The authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-4323-2541
                Article
                viruses-10-00271
                10.3390/v10050271
                5977264
                29783672
                04178f01-8943-4a24-9649-a93db4c5bf9d
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 March 2018
                : 15 May 2018
                Categories
                Article

                Microbiology & Virology
                marek’s diseases virus,avian leukosis virus subgroup j,superinfection,synergism,pathogenicity

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