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      Piscirickettsia salmonis Imbalances the Innate Immune Response to Succeed in a Productive Infection in a Salmonid Cell Line Model

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          Abstract

          Piscirickettsia salmonis is a facultative intracellular bacterium that causes the disease called “salmon rickettsial syndrome”. Attempts to control this disease have been unsuccessful, because existing vaccines have not achieved the expected effectiveness and the antibiotics used fail to completely eradicate the pathogen. This is in part the product of lack of scientific information that still lacks on the mechanisms used by this bacterium to overcome infected–cell responses and survive to induce a productive infection in macrophages. For that, this work was focused in determining if P. salmonis is able to modify the expression and the imbalance of IL-12 and IL-10 using an in vitro model. Additionally, we also evaluated the role the antimicrobial peptide hepcidin had in the control of this pathogen in infected cells. Therefore, the expression of IL-10 and IL-12 was evaluated at earlier stages of infection in the RTS11 cell line derived from O ncorhynchus mykiss macrophages. Simultaneously, the hepcidin expression and location was analyzed in the macrophages infected with the pathogen. Our results suggest that IL-10 is clearly induced at early stages of infection with values peaking at 36 hours post infection. Furthermore, infective P. salmonis downregulates the expression of antimicrobial peptide hepcidin and vesicles containing this peptide were unable to merge with the infective bacteria. Our results suggest that P. salmonis is able to manipulate the behavior of host cytokines and likely might constitute a virulence mechanism that promotes intracellular bacterial replication in leukocytes cells lines of trout and salmon. This mechanism involves the generation of an optimum environment for the microorganism and the downregulation of antimicrobial effectors like hepcidin.

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          Most cited references45

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          Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

          In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.
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            A semi-empirical method for prediction of antigenic determinants on protein antigens.

            Analysis of data from experimentally determined antigenic sites on proteins has revealed that the hydrophobic residues Cys, Leu and Val, if they occur on the surface of a protein, are more likely to be a part of antigenic sites. A semi-empirical method which makes use of physicochemical properties of amino acid residues and their frequencies of occurrence in experimentally known segmental epitopes was developed to predict antigenic determinants on proteins. Application of this method to a large number of proteins has shown that our method can predict antigenic determinants with about 75% accuracy which is better than most of the known methods. This method is based on a single parameter and thus very simple to use.
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              General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids.

              R Houghten (1985)
              A novel yet simple method is described that facilitates the synthesis of large numbers of peptides to the extent that the synthesis process need no longer be the limiting factor in many studies involving peptides. By using the methods described, 10-20 mg of 248 different 13-residue peptides representing single amino acid variants of a segment of the hemagglutinin protein (HA1) have been prepared and characterized in less than 4 weeks. Through examination of the binding of these analogs to monoclonal antibodies raised against residues 75-110 of HA1, it was found that a single amino acid, aspartic acid at position 101, is of unique importance to the interaction. Two other residues, aspartic acid-104 and alanine-106, were found to play a lesser but significant role in the binding interaction. Other single positional residue variations appear to be of little or no importance.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 October 2016
                2016
                : 11
                : 10
                : e0163943
                Affiliations
                [1 ]Laboratorio de Genética e Inmunología Molecular, Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
                [2 ]Fraunhofer Chile Research Foundation, Center for Systems Biotechnology, Las Condes, Santiago, Chile
                Institute of Infectiology, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: CAA FG LM SM.

                • Data curation: CAA FG.

                • Formal analysis: CAA FG SM LM.

                • Funding acquisition: CAA FG LM.

                • Investigation: CAA FG RR.

                • Methodology: CAA FG SM.

                • Resources: CAA FG SM LM.

                • Supervision: SM LM.

                • Validation: CAA FG RR.

                • Visualization: CAA RR.

                • Writing – original draft: CAA FG SM LM.

                • Writing – review & editing: CAA FG.

                Article
                PONE-D-16-06224
                10.1371/journal.pone.0163943
                5056700
                27723816
                6545efe1-a410-4e9c-8712-ec24195bdacb
                © 2016 Álvarez et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 February 2016
                : 16 September 2016
                Page count
                Figures: 5, Tables: 0, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;
                Award ID: 111305407
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;
                Award ID: 1140797
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002848, Comisión Nacional de Investigación Científica y Tecnológica;
                Award ID: Beca Nacional de Doctorado
                Award Recipient :
                Support was provided by: 1)Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), Grantt 11130407 to FAG ( www.conicyt.cl); 2)Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), Grantt 1140797 to LM ( www.conicyt.cl); 3)Beca CONICYT para doctorados Nacionales to CAA.
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