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      Combination of TLR2 and TLR3 agonists derepress infectious bursal disease virus vaccine-induced immunosuppression in the chicken

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          Abstract

          Live intermediate plus infectious bursal disease virus (IBDV) vaccines (hot vaccines) are used for protection against the virulent IBDV strains in young chickens. We evaluated the potential of Toll-like receptor (TLR) agonists to alleviate hot vaccine-induced immunosuppression. The combination of Pam3CSK4 and poly I:C synergistically upregulated IFN-β, IFN-γ, IL-12, IL-4, and IL-13 transcripts and cross-inhibited IL-1β, IL-10, and iNOS transcripts in the chicken peripheral blood mononuclear cells (PBMCs) as analyzed by quantitative real-time PCR. Further, four-week old specific pathogen free White Leghorn chickens ( n = 60) were randomly divided into six groups and either immunized with hot IBDV vaccine with or without Pam3CSK4 and/or poly I:C or not vaccinated to serve as controls. The results indicated that poly I:C alone and in combination with Pam3CSK4 alleviated vaccine-induced immunosuppression, as evidenced by greater weight gain, increased overall antibody responses to both sheep erythrocytes and live infectious bronchitis virus vaccine, upregulated IFN-γ transcripts and nitric oxide production by PBMCs ( P < 0.05), and lower bursal lesion score in the experimental birds. In conclusion, poly I:C alone and its combination with Pam3CSK4 reduced the destruction of B cells as well as bursal damage with restoration of function of T cells and macrophages when used with a hot IBDV vaccine.

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          Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells.

          Toll-like receptors (TLRs) sense microbial products and initiate adaptive immune responses by activating dendritic cells (DCs). As pathogens may contain several TLR agonists, we sought to determine whether different TLRs cooperate in DC activation. In human and mouse DCs, TLR3 and TLR4 potently acted in synergy with TLR7, TLR8 and TLR9 in the induction of a selected set of genes. Synergic TLR stimulation increased production of interleukins 12 and 23 and increased the Delta-4/Jagged-1 ratio, leading to DCs with enhanced and sustained T helper type 1-polarizing capacity. Global gene transcriptional analysis showed that TLR synergy 'boosted' only approximately 1% of the transcripts induced by single TLR agonists. These results identify a 'combinatorial code' by which DCs discriminate pathogens and suggest new strategies for promoting T helper type 1 responses.
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            Toll-like receptor signaling inhibits hepatitis B virus replication in vivo.

            Toll-like receptors (TLR) play a key role in innate immunity. To examine the ability of diverse TLRs to modulate hepatitis B virus (HBV) replication, HBV transgenic mice received a single intravenous injection of ligands specific for TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9. All of the ligands except for TLR2 inhibited HBV replication in the liver noncytopathically within 24 h in a alpha/beta interferon-dependent manner. The ability of these TLR ligands to induce antiviral cytokines at the site of HBV replication suggests that TLR activation could represent a powerful and novel therapeutic strategy for the treatment of chronic HBV infection.
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              Infectious bursal disease virus of chickens: pathogenesis and immunosuppression.

              Infectious bursal disease virus (IBDV) is an important immunosuppressive virus of chickens. The virus is ubiquitous and, under natural conditions, chickens acquire infection by the oral route. IgM+ cells serve as targets for the virus. The most extensive virus replication takes place in the bursa of Fabricius. The acute phase of the disease lasts for about 7-10 days. Within this phase, bursal follicles are depleted of B cells and the bursa becomes atrophic. Abundant viral antigen can be detected in the bursal follicles and other peripheral lymphoid organs such as the cecal tonsils and spleen. CD4(+) and CD8(+) T cells accumulate at and near the site of virus replication. The virus-induced bursal T cells are activated, exhibit upregulation of cytokine genes, proliferate in response to in vitro stimulation with IBDV and have suppressive properties. Chickens may die during the acute phase of the disease although IBDV induced mortality is highly variable and depends, among other factors, upon the virulence of the virus strain. Chickens that survive the acute disease clear the virus and recover from its pathologic effects. Bursal follicles are repopulated with IgM(+) B cells. Clinical and subclinical infection with IBDV may cause immunosuppression. Both humoral and cellular immune responses are compromised. Inhibition of the humoral immunity is attributed to the destruction of immunoglobulin-producing cells by the virus. Other mechanisms such as altered antigen-presenting and helper T cell functions may also be involved. Infection with IBDV causes a transient inhibition of the in vitro proliferative response of T cells to mitogens. This inhibition is mediated by macrophages which are activated in virus-exposed chickens and exhibit a marked enhancement of expression of a number of cytokine genes. We speculate that T cell cytokines such as interferon (IFN)-gamma may stimulate macrophages to produce nitric oxide (NO) and other cytokines with anti-proliferative activity. Additional studies are needed to identify the possible direct immunosuppressive effect of IBDV on T cells and their functions. Studies are also needed to examine effects of the virus on innate immunity. Earlier data indicate that the virus did not affect normal natural killer (NK) cell levels in chickens.
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                Author and article information

                Contributors
                dearsaromib@yahoo.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                3 June 2019
                3 June 2019
                2019
                : 9
                : 8197
                Affiliations
                [1 ]ISNI 0000 0000 9070 5290, GRID grid.417990.2, Immunology Section, , ICAR - Indian Veterinary Research Institute, Izatnagar, ; Bareilly, Uttar Pradesh (243 122) India
                [2 ]ISNI 0000 0000 9070 5290, GRID grid.417990.2, Division of Pathology, , ICAR - Indian Veterinary Research Institute, Izatnagar, ; Bareilly, Uttar Pradesh (243 122) India
                [3 ]ISNI 0000 0000 9070 5290, GRID grid.417990.2, Division of Animal Biochemistry, , ICAR - Indian Veterinary Research Institute, Izatnagar, ; Bareilly, Uttar Pradesh (243 122) India
                [4 ]ISNI 0000 0000 9070 5290, GRID grid.417990.2, Division of Animal Reproduction, , ICAR - Indian Veterinary Research Institute, Izatnagar, ; Bareilly, Uttar Pradesh (243 122) India
                [5 ]ISNI 0000 0000 9070 5290, GRID grid.417990.2, Division of Veterinary Biotechnology, , ICAR - Indian Veterinary Research Institute, Izatnagar, ; Bareilly, Uttar Pradesh (243 122) India
                [6 ]ISNI 0000 0000 9070 5290, GRID grid.417990.2, Centre for Animal Disease Research and Diagnosis, , ICAR - Indian Veterinary Research Institute, Izatnagar, ; Bareilly, Uttar Pradesh (243 122) India
                Author information
                http://orcid.org/0000-0001-7641-5067
                Article
                44578
                10.1038/s41598-019-44578-5
                6547722
                31160675
                3b25441f-ffe5-45d3-a086-fbde011be3da
                © The Author(s) 2019

                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
                : 4 January 2019
                : 20 May 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001407, Department of Biotechnology, Ministry of Science and Technology (DBT);
                Award ID: No. BT/PR15618/ADV/90/202/2016
                Award Recipient :
                Categories
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                © The Author(s) 2019

                Uncategorized
                toll-like receptors,adjuvants
                Uncategorized
                toll-like receptors, adjuvants

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