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      Identification of single nucleotide polymorphisms in Toll-like receptor candidate genes associated with tuberculosis infection in water buffalo ( Bubalus bubalis)

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          Abstract

          Background

          Toll-like receptors play a key role in innate immunity by recognizing pathogens and activating appropriate responses. Pathogens express several signal molecules (pathogen-associated molecular patterns, PAMPs) essential for survival and pathogenicity. Recognition of PAMPs triggers an array of anti-microbial immune responses through the induction of various inflammatory cytokines. The objective of this work was to perform a case-control study to characterize the distribution of polymorphisms in three candidate genes ( toll-like receptor 2, toll-like receptor 4, toll-like receptor 9) and to test their role as potential risk factors for tuberculosis infection in water buffalo ( Bubalus bubalis).

          Results

          The case-control study included 184 subjects, 59 of which resulted positive to both intradermal TB test and Mycobacterium bovis isolation (cases) and 125 resulted negative to at least three consecutive intradermal TB tests. The statistical analysis indicated that two polymorphisms exhibited significant differences in allelic frequencies between cases and controls. Indeed, the TT genotype at TLR9 2340 C > T locus resulted significantly associated with susceptibility to bovine tuberculosis ( P = 0.030, OR = 3.31, 95% CI = 1.05-10.40). One polymorphism resulted significantly associated with resistance to the disease, and included the CC genotype, at the TLR4 672 A > C locus ( P = 0.01, OR = 0.26, 95% CI = 0.08-0.80). Haplotype reconstruction of the TLR2 gene revealed one haplotype (CTTACCAGCGGCCAGTCCC) associated with disease resistance ( P = 0.04, OR = 0.51, 95% CI = 0.27–0.96), including the allelic variant associated with disease resistance.

          Conclusions

          The work describes novel mutations in bubaline TLR2, TLR4 and TLR9 genes and presents their association with M. bovis infection. These results will enhance our ability to determine the risk of developing the disease by improving the knowledge of the immune mechanisms involved in host response to mycobacterial infection, and will allow the creation of multiple layers of disease resistance in herds by selective breeding.

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          Most cited references32

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          Toll-like receptors: critical proteins linking innate and acquired immunity.

          Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
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            CDD: specific functional annotation with the Conserved Domain Database

            NCBI's Conserved Domain Database (CDD) is a collection of multiple sequence alignments and derived database search models, which represent protein domains conserved in molecular evolution. The collection can be accessed at http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml, and is also part of NCBI's Entrez query and retrieval system, cross-linked to numerous other resources. CDD provides annotation of domain footprints and conserved functional sites on protein sequences. Precalculated domain annotation can be retrieved for protein sequences tracked in NCBI's Entrez system, and CDD's collection of models can be queried with novel protein sequences via the CD-Search service at http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi. Starting with the latest version of CDD, v2.14, information from redundant and homologous domain models is summarized at a superfamily level, and domain annotation on proteins is flagged as either ‘specific’ (identifying molecular function with high confidence) or as ‘non-specific’ (identifying superfamily membership only).
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              CDD: a Conserved Domain Database for the functional annotation of proteins

              NCBI’s Conserved Domain Database (CDD) is a resource for the annotation of protein sequences with the location of conserved domain footprints, and functional sites inferred from these footprints. CDD includes manually curated domain models that make use of protein 3D structure to refine domain models and provide insights into sequence/structure/function relationships. Manually curated models are organized hierarchically if they describe domain families that are clearly related by common descent. As CDD also imports domain family models from a variety of external sources, it is a partially redundant collection. To simplify protein annotation, redundant models and models describing homologous families are clustered into superfamilies. By default, domain footprints are annotated with the corresponding superfamily designation, on top of which specific annotation may indicate high-confidence assignment of family membership. Pre-computed domain annotation is available for proteins in the Entrez/Protein dataset, and a novel interface, Batch CD-Search, allows the computation and download of annotation for large sets of protein queries. CDD can be accessed via http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml.
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                Author and article information

                Contributors
                flora.alfano@cert.izsmportici.it
                simone.peletto@izsto.it
                mariagabriella.lucibelli@cert.izsmportici.it
                giorgia.borriello@izsmportici.it
                giovanna.urciuolo@tiscali.it
                mariagrazia.maniaci@izsto.it
                rosanna.desiato@izsto.it
                michela.tarantino@iss.it
                ambarone@unina.it
                paolo.pasquali@iss.it
                pierluigi.acutis@izsto.it
                giorgio.galiero@cert.izsmportici.it
                Journal
                BMC Genet
                BMC Genet
                BMC Genetics
                BioMed Central (London )
                1471-2156
                14 December 2014
                14 December 2014
                2014
                : 15
                : 1
                : 139
                Affiliations
                [ ]Istituto Zooprofilattico Sperimentale del Mezzogiorno, Via Salute, 2, 80055, Portici, Italy
                [ ]Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle d’Aosta, Via Bologna, 148, 10154 Torino, Italy
                [ ]Istituto Superiore di Sanità, Dipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare, Viale Regina Elena, 299, 00161 Roma, Italy
                [ ]Dipartimento di Agraria, Università degli Studi di Napoli “Federico II”, Via Università 100, 80055 Portici, Italy
                Article
                139
                10.1186/s12863-014-0139-y
                4278265
                25496717
                88dd9d23-94fe-4aad-a5fc-d39a16c965ae
                © Alfano et al.; licensee BioMed Central. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 March 2014
                : 27 November 2014
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2014

                Genetics
                bubalus bubalis,tlrs,genetic resistance,case–control study
                Genetics
                bubalus bubalis, tlrs, genetic resistance, case–control study

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