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1.
PLoS One ; 14(2): e0212067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30763354

RESUMO

Bovine tuberculosis (bTB) is an infectious disease of cattle generally caused by Mycobacterium bovis, a bacterium that can elicit disease humans. Since the 1950s, the objective of the national bTB eradication program in Republic of Ireland was the biological extinction of bTB; that purpose has yet to be achieved. Objectives of the present study were to develop the statistical methodology and variance components to undertake routine genetic evaluations for resistance to bTB; also of interest was the detection of regions of the bovine genome putatively associated with bTB infection in dairy and beef breeds. The novelty of the present study, in terms of research on bTB infection, was the use of beef breeds in the genome-wide association and the utilization of imputed whole genome sequence data. Phenotypic bTB data on 781,270 animals together with imputed whole genome sequence data on 7,346 of these animals' sires were available. Linear mixed models were used to quantify variance components for bTB and EBVs were validated. Within-breed and multi-breed genome-wide associations were undertaken using a single-SNP regression approach. The estimated genetic standard deviation (0.09), heritability (0.12), and repeatability (0.30) substantiate that genetic selection help to eradicate bTB. The multi-breed genome-wide association analysis identified 38 SNPs and 64 QTL regions associated with bTB infection; two QTL regions (both on BTA23) identified in the multi-breed analysis overlapped with the within-breed analyses of Charolais, Limousin, and Holstein-Friesian. Results from the association analysis, coupled with previous studies, suggest bTB is controlled by an infinitely large number of loci, each having a small effect. The methodology and results from the present study will be used to develop national genetic evaluations for bTB in the Republic of Ireland. In addition, results can also be used to help uncover the biological architecture underlying resistance to bTB infection in cattle.


Assuntos
Estudo de Associação Genômica Ampla , Tuberculose Bovina/genética , Sequenciamento Completo do Genoma , Análise de Variância , Animais , Bovinos , Genótipo , Fenótipo , Polimorfismo de Nucleotídeo Único
2.
Int J Mol Sci ; 20(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577452

RESUMO

It is widely accepted that different strains of Mycobacterium tuberculosis have variable degrees of pathogenicity and induce different immune responses in infected hosts. Similarly, different strains of Mycobacterium bovis have been identified but there is a lack of information regarding the degree of pathogenicity of these strains and their ability to provoke host immune responses. Therefore, in the current study, we used a mouse model to evaluate various factors involved in the severity of disease progression and the induction of immune responses by two strains of M. bovis isolated from cattle. Mice were infected with both strains of M. bovis at different colony-forming unit (CFU) via inhalation. Gross and histological findings revealed more severe lesions in the lung and spleen of mice infected with M. bovis N strain than those infected with M. bovis C68004 strain. In addition, high levels of interferon-γ (IFN-γ), interleukin-17 (IL-17), and IL-22 production were observed in the serum samples of mice infected with M. bovis N strain. Comparative genomic analysis showed the existence of 750 single nucleotide polymorphisms and 145 small insertions/deletions between the two strains. After matching with the Virulence Factors Database, mutations were found in 29 genes, which relate to 17 virulence factors. Moreover, we found an increased number of virulent factors in M. bovis N strain as compared to M. bovis C68004 strain. Taken together, our data reveal that variation in the level of pathogenicity is due to the mutation in the virulence factors of M. bovis N strain. Therefore, a better understanding of the mechanisms of mutation in the virulence factors will ultimately contribute to the development of new strategies for the control of M. bovis infection.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Mycobacterium bovis , Tuberculose Bovina/genética , Tuberculose Bovina/microbiologia , Animais , Biópsia , Bovinos , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/genética , Pulmão/patologia , Camundongos , Tipagem de Sequências Multilocus , Mutação , Mycobacterium bovis/classificação , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Polimorfismo de Nucleotídeo Único , Baço/patologia , Tuberculose Bovina/imunologia , Virulência/genética , Fatores de Virulência
4.
Vet J ; 232: 1-5, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29428082

RESUMO

Cluster differentiation antigen 14 (CD14) is an important pattern recognition receptor protein in innate immunity. The aim of this study was to identify and assess the association of single-nucleotide polymorphisms (SNPs) in the CD14 gene with susceptibility to bovine tuberculosis (BTB) in Chinese Holstein cows. DNA samples from 517 Chinese Holstein cows (257 tuberculosis positive cases and 259 healthy controls) were collected from dairy farms in China. SNPs in the entire CD14 gene, including exonic regions, intronic regions and close to the 5'- and 3'-terminal untranslated regions, were detected by PCR, followed by direct sequencing. Five SNPs (-5C/T, 613G/A, 1023G/A, 1306G/A and 1326G/T) were found in the CD14 gene region. Significantly increased BTB susceptibility was evident in T allele carriers of -5C/T (P<0.001; odds ratio, OR 2.02; 95% confidence interval, CI 1.57-2.77), G allele carriers of 613G/A (P<0.001; OR 2.17, 95% CI 1.50-3.08) and TG haplotype carriers of both SNPs (P<0.001; OR 3.14, 95% CI 1.24-4.50). These results suggest that -5C/T and 613G/A are risk factors for BTB in Chinese Holstein cattle and might be used as candidate genetic markers in breeding cows with natural resistance to BTB.


Assuntos
Bovinos/genética , Predisposição Genética para Doença/genética , Receptores de Lipopolissacarídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Tuberculose Bovina/genética , Animais , China , DNA , Feminino , Técnicas de Genotipagem/veterinária , Haplótipos
5.
Anim Genet ; 49(2): 103-109, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29368428

RESUMO

Genetic selection of cattle more resistant to bovine tuberculosis (bTB) may offer a complementary control strategy. Hypothesising underlying non-additive genetic variation, we present an approach using genome-wide high density markers to identify genomic loci with dominance effects on bTB resistance and to test previously published regions with heterozygote advantage in bTB. Our data comprised 1151 Holstein-Friesian cows from Northern Ireland, confirmed bTB cases and controls, genotyped with the 700K Illumina BeadChip. Genome-wide markers were tested for associations between heterozygosity and bTB status using marker-based relationships. Results were tested for robustness against genetic structure, and the genotypic frequencies of a significant locus were tested for departures from Hardy-Weinberg equilibrium. Genomic regions identified in our study and in previous publications were tested for dominance effects. Genotypic effects were estimated through ASReml mixed models. A SNP (rs43032684) on chromosome 6 was significant at the chromosome-wide level, explaining 1.7% of the phenotypic variance. In the controls, there were fewer heterozygotes for rs43032684 (P < 0.01) with the genotypic values suggesting that heterozygosity confers a heterozygote disadvantage. The region surrounding rs43032684 had a significant dominance effect (P < 0.01). SNP rs43032684 resides within a pseudogene with a parental gene involved in macrophage response to infection and within a copy-number-variation region previously associated with nematode resistance. No dominance effect was found for the region on chromosome 11, as indicated by a previous candidate region bTB study. These findings require further validation with large-scale data.


Assuntos
Bovinos/genética , Resistência à Doença/genética , Genética Populacional , Tuberculose Bovina/genética , Animais , Bovinos/microbiologia , Indústria de Laticínios , Estudo de Associação Genômica Ampla/veterinária , Genótipo , Heterozigoto , Irlanda , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
6.
Stat Med ; 36(18): 2875-2886, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28493332

RESUMO

As p-values are the most common measures of evidence against a hypothesis, their calibration with respect to null hypothesis conditional probability is important in order to match frequentist unconditional inference with the Bayesian ones. The Selke, Bayarri and Berger calibration is one of the most popular attempts to obtain such a calibration. This relies on the theoretical sampling null distribution of p-values, which is the well-known Uniform(0,1), but arising only for specific sampling models. We generalize this calibration by considering a sampling null distribution estimated from the data. It is possible to obtain such an empirical null distribution, for instance, in the context of multiple testing in which many p-values come from the null model. Such a context is purely instrumental for the purposes of p-value calibration, and multiple testing still needs to be considered with appropriate techniques. The new calibration proposed here still remains a simple analytic formula like the original one under the Uniform(0,1) and basically provides a stronger interpretation framework for the widely used p-value. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Modelos Estatísticos , Animais , Teorema de Bayes , Bioestatística , Bovinos , Humanos , Macrófagos/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Probabilidade , Neoplasias da Próstata/genética , Análise de Sequência de RNA/estatística & dados numéricos , Estatísticas não Paramétricas , Tuberculose Bovina/genética
7.
Vet Immunol Immunopathol ; 186: 51-54, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28413050

RESUMO

This study evaluated whether there was an association between polymorphisms within the Toll-like receptor 2 gene (TLR2) of Chinese Holstein cattle and susceptibility to bovine tuberculosis (BTB). In a case-control study including 210 BTB cases and 237 control cattle, we found only two common single-nucleotide polymorphisms (SNPs) within the entire coding region of the TLR2 gene, A631G (rs95214857) and T1707C (rs1388116488). Additionally, the allele and genotype distributions of A631G and T1707C were not different between case and control groups, indicated that these SNPs were not associated with susceptibility to BTB. These results suggested that polymorphisms in the TLR2 gene might not play a significant role in the BTB risk in Chinese Holstein cattle.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptor 2 Toll-Like/genética , Tuberculose Bovina/genética , Animais , Bovinos , China
8.
Tuberculosis (Edinb) ; 104: 87-94, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28454655

RESUMO

Understanding the role of wildlife in the maintenance or spread of emerging infectious diseases is a growing priority across the world. Bovine tuberculosis (BTB) is a chronic, infectious disease caused by Mycobacterium bovis (M. bovis). BTB is widespread within game reserves in southern Africa, and within these ecosystems the primary wildlife host of this disease is the African buffalo. We used a modified bacterial killing assay for mycobacteria to investigate the effect of Toll-like receptor (TLR) genetic diversity and demographic parameters on the ability of African buffalo to restrict mycobacterial growth. Eosinophil count, time delay, bovine PPD response and avian PPD response were negatively correlated with mycobacterial growth. TLR6 diversity and the interaction of age group and sex were positively correlated with mycobacterial growth. Our results suggest that both demographic and individual immune parameters influence the ability to control mycobacterial infection in African buffalo. TLR6 diversity is particularly interesting as this locus has also shown associations with BTB in cattle, suggesting that further research into the effects, selection and role of TLR6 variants in bovine tuberculosis will be productive.


Assuntos
Búfalos/genética , Variação Genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Receptores Toll-Like/genética , Tuberculose Bovina/microbiologia , Animais , Carga Bacteriana , Búfalos/imunologia , Búfalos/microbiologia , Bovinos , Feminino , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Masculino , Viabilidade Microbiana , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Fenótipo , Receptor 6 Toll-Like/genética , Receptor 6 Toll-Like/imunologia , Receptores Toll-Like/imunologia , Tuberculose Bovina/genética , Tuberculose Bovina/imunologia , Tuberculose Bovina/transmissão
9.
BMC Genet ; 18(1): 27, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28335717

RESUMO

BACKGROUND: The significant social and economic loss as a result of bovine tuberculosis (bTB) presents a continuous challenge to cattle industries in the UK and worldwide. However, host genetic variation in cattle susceptibility to bTB provides an opportunity to select for resistant animals and further understand the genetic mechanisms underlying disease dynamics. METHODS: The present study identified genomic regions associated with susceptibility to bTB using genome-wide association (GWA), regional heritability mapping (RHM) and chromosome association approaches. Phenotypes comprised de-regressed estimated breeding values of 804 Holstein-Friesian sires and pertained to three bTB indicator traits: i) positive reactors to the skin test with positive post-mortem examination results (phenotype 1); ii) positive reactors to the skin test regardless of post-mortem examination results (phenotype 2) and iii) as in (ii) plus non-reactors and inconclusive reactors to the skin tests with positive post-mortem examination results (phenotype 3). Genotypes based on the 50 K SNP DNA array were available and a total of 34,874 SNPs remained per animal after quality control. RESULTS: The estimated polygenic heritability for susceptibility to bTB was 0.26, 0.37 and 0.34 for phenotypes 1, 2 and 3, respectively. GWA analysis identified a putative SNP on Bos taurus autosomes (BTA) 2 associated with phenotype 1, and another on BTA 23 associated with phenotype 2. Genomic regions encompassing these SNPs were found to harbour potentially relevant annotated genes. RHM confirmed the effect of these genomic regions and identified new regions on BTA 18 for phenotype 1 and BTA 3 for phenotypes 2 and 3. Heritabilities of the genomic regions ranged between 0.05 and 0.08 across the three phenotypes. Chromosome association analysis indicated a major role of BTA 23 on susceptibility to bTB. CONCLUSION: Genomic regions and candidate genes identified in the present study provide an opportunity to further understand pathways critical to cattle susceptibility to bTB and enhance genetic improvement programmes aiming at controlling and eradicating the disease.


Assuntos
Predisposição Genética para Doença/genética , Genômica , Tuberculose Bovina/genética , Animais , Bovinos , Mapeamento Cromossômico , Cromossomos de Mamíferos/genética , Estudo de Associação Genômica Ampla
10.
Tuberculosis (Edinb) ; 103: 10-15, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28237028

RESUMO

We investigated the associations between SLC11A1 polymorphisms and susceptibility to tuberculosis (TB) in Chinese Holstein cattle, using a case-control study of 136 animals that had positive reactions to TB tests and showed symptoms and 96 animals that had negative reactions to tests and showed no symptoms. Polymerase chain reaction (PCR) sequencing and the restriction fragment length polymorphism (RFLP) technique were used to detect and determine SLC11A1 polymorphisms. Association analysis identified significant correlations between SLC11A1 polymorphisms and susceptibility/resistance to TB, and two genetic markers for SLC11A1 were established using PCR-RFLP. Sequence alignment of SLC11A1 revealed seven single-nucleotide polymorphisms (SNPs). This is the first report of MaeII PCR-RFLP markers for the SLC11A1-SNP3 site and PstI PCR-RFLP markers for the SLC11A1-SNP5 and SLC11A1-SNP6 sites in Chinese Holstein cattle. Logistic regression analysis indicated that SLC11A1-SNP1, SLC11A1-SNP3, and SLC11A1-SNP5 were significantly associated with susceptibility/resistance to TB. Two genotypes of SLC11A1-SNP3 were susceptible to TB, whereas one genotype of SLC11A1-SNP1 and two genotypes of SLC11A1-SNP5 were resistant. Haplotype analysis showed that nine haplotypes were potentially resistant to TB. After Bonferroni correction, three of the haplotypes remained significantly associated with TB resistance. SLC11A1 is a useful candidate gene related to TB in Chinese Holstein cattle.


Assuntos
Análise do Polimorfismo de Comprimento de Fragmentos Amplificados/veterinária , Proteínas de Transporte de Cátions/genética , Mycobacterium bovis/patogenicidade , Polimorfismo de Nucleotídeo Único , Tuberculose Bovina/genética , Animais , Bovinos , China , Indústria de Laticínios , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Desequilíbrio de Ligação , Modelos Logísticos , Razão de Chances , Fenótipo , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Tuberculose Bovina/diagnóstico , Tuberculose Bovina/microbiologia
11.
Immunol Cell Biol ; 95(5): 436-442, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27833091

RESUMO

Mycobacterium bovis, the causative agent of bovine tuberculosis (TB), is a successful pathogen that remains an important global threat to livestock. Cattle naturally exposed to M. bovis normally become reactive to the M. bovis-purified protein derivative (tuberculin) skin test; however, some individuals remain negative, suggesting that they may be resistant to infection. To better understand host innate resistance to infection, 26 cattle from herds with a long history of high TB prevalence were included in this study. We investigated the bactericidal activity, the production of reactive oxygen and nitrogen species and the TB-related gene expression profile after in vitro M. bovis challenge of monocyte-derived macrophages from cattle with TB (n=17) and from non-infected, exposed cattle (in-contacts, n=9). The disease status was established based on the tuberculin skin test and blood interferon-gamma test responses, the presence of visible lesions at inspection on abattoirs and the histopathology and culture of M. bovis. Although macrophages from TB-infected cattle enabled M. bovis replication, macrophages from healthy, exposed cattle had twofold lower bacterial loads, overproduced nitric oxide and had lower interleukin (IL)-10 gene expression (P⩽0.05). Higher mRNA expression levels of inducible nitric oxide synthase, C-C motif chemokine ligand 2 and IL-12 were observed in macrophages from all in-contact cattle than in macrophages from their TB-infected counterparts, which expressed more tumour necrosis factor-α; however, the differences were not statistically significant owing to individual variation. These results confirm that macrophage bactericidal responses have a crucial role in innate resistance to M. bovis infection in cattle.


Assuntos
Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium bovis/fisiologia , Tuberculose Bovina/imunologia , Tuberculose Bovina/microbiologia , Animais , Bovinos , Sobrevivência Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Feminino , Regulação da Expressão Gênica , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fagocitose , Superóxidos/metabolismo , Tuberculose Bovina/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
Microb Pathog ; 103: 57-64, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28007592

RESUMO

Bovine colostrum contains compounds, which provide passive immune protection from mother to newborn calves. Little is known about cytokine levels and their role in bovine colostrum. Moreover, the capacity of bovine colostrum cells to mount specific immune responses after natural exposure to bovine tuberculosis (bTB) antigens in dairy herds has not been studied, thus far. The purpose of this study was to identify biomarkers for bTB infection measurable in bovine colostrum. The present study reveals that isolated-immune colostrum cells can mount a specific immune response against bTB antigens, by measuring the novo IFN-γ release in cell culture. We found that IFN-γ levels in the responders (Bov+) to bTB antigen were higher than in non-responders (Bov-). On the other hand, proinflammatory cytokines contained in colostrum's whey were tested in Tuberculin Skin Test (TST) reactor (TST+) and non-reactor (TST-) animals to assess their potential role as biomarker. We observed that IFN-γ levels were lower or undetectable, as opposed to IL4 levels were measurable, the TNF-α level was higher in TST- than TST+, while IL-6 levels showed the opposite reaction and with no statistical significance. Moreover, IL-1α mRNA expression levels were higher in colostrum mononuclear cells (CMC) in Bov+ cattle. Collectively, these data suggest that the differential expression of pro and anti-inflammatory cytokines could have relevant value to diagnose bTB in cattle.


Assuntos
Biomarcadores , Colostro/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Mycobacterium bovis/imunologia , Tuberculose Bovina/imunologia , Tuberculose Bovina/metabolismo , Animais , Antígenos de Bactérias/imunologia , Bovinos , Citocinas/genética , Feminino , Expressão Gênica , Testes de Liberação de Interferon-gama , Tuberculose Bovina/genética
13.
Genet Sel Evol ; 48(1): 90, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27884111

RESUMO

BACKGROUND: Bovine tuberculosis (bTB) is a disease of significant economic importance and is a persistent animal health problem with implications for public health worldwide. Control of bTB in the UK has relied on diagnosis through the single intradermal comparative cervical test (SICCT). However, limitations in the sensitivity of this test hinder successful eradication and the control of bTB remains a major challenge. Genetic selection for cattle that are more resistant to bTB infection can assist in bTB control. The aim of this study was to conduct a quantitative genetic analysis of SICCT measurements collected during bTB herd testing. Genetic selection for bTB resistance will be partially informed by SICCT-based diagnosis; therefore it is important to know whether, in addition to increasing bTB resistance, this might also alter genetically the epidemiological characteristics of SICCT. RESULTS: Our main findings are that: (1) the SICCT test is robust at the genetic level, since its hierarchy and comparative nature provide substantial protection against random genetic changes that arise from genetic drift and from correlated responses among its components due to either natural or artificial selection; (2) the comparative nature of SICCT provides effective control for initial skin thickness and age-dependent differences; and (3) continuous variation in SICCT is only lowly heritable and has a weak correlation with SICCT positivity among healthy animals which was not significantly different from zero (P > 0.05). These emerging results demonstrate that genetic selection for bTB resistance is unlikely to change the probability of correctly identifying non-infected animals, i.e. the test's specificity, while reducing the overall number of cases. CONCLUSIONS: This study cannot exclude all theoretical risks from selection on resistance to bTB infection but the role of SICCT in disease control is unlikely to be rapidly undermined, with any adverse correlated responses expected to be weak and slow, which allow them to be monitored and managed.


Assuntos
Cruzamento/estatística & dados numéricos , Resistência à Doença/genética , Padrões de Herança , Teste Tuberculínico/estatística & dados numéricos , Tuberculose Bovina/diagnóstico , Tuberculose Bovina/genética , Fatores Etários , Animais , Bovinos , Feminino , Testes Genéticos , Masculino , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/isolamento & purificação , Pregas Cutâneas , Tuberculose Bovina/microbiologia
14.
Genet Sel Evol ; 48: 19, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26960806

RESUMO

BACKGROUND: Bovine tuberculosis (bTB) infection in cattle is a significant economic concern in many countries, with annual costs to the UK and Irish governments of approximately €190 million and €63 million, respectively, for bTB control. The existence of host additive and non-additive genetic components to bTB susceptibility has been established. METHODS: Two approaches i.e. single-SNP (single nucleotide polymorphism) regression and a Bayesian method were applied to genome-wide association studies (GWAS) using high-density SNP genotypes (n = 597,144 SNPs) from 841 dairy artificial insemination (AI) sires. Deregressed estimated breeding values for bTB susceptibility were used as the quantitative dependent variable. Network analysis was performed using the quantitative trait loci (QTL) that were identified as significant in the single-SNP regression and Bayesian analyses separately. In addition, an identity-by-descent analysis was performed on a subset of the most prolific sires in the dataset that showed contrasting prevalences of bTB infection in daughters. RESULTS: A significant QTL region was identified on BTA23 (P value >1 × 10(-5), Bayes factor >10) across all analyses. Sires with the minor allele (minor allele frequency = 0.136) for this QTL on BTA23 had estimated breeding values that conferred a greater susceptibility to bTB infection than those that were homozygous for the major allele. Imputation of the regions that flank this QTL on BTA23 to full sequence indicated that the most significant associations were located within introns of the FKBP5 gene. CONCLUSIONS: A genomic region on BTA23 that is strongly associated with host susceptibility to bTB infection was identified. This region contained FKBP5, a gene involved in the TNFα/NFκ-B signalling pathway, which is a major biological pathway associated with immune response. Although there is no study that validates this region in the literature, our approach represents one of the most powerful studies for the analysis of bTB susceptibility to date.


Assuntos
Cromossomos de Mamíferos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/veterinária , Locos de Características Quantitativas , Tuberculose Bovina/genética , Alelos , Animais , Teorema de Bayes , Cruzamento , Bovinos , Indústria de Laticínios , Feminino , Genótipo , Irlanda , Masculino , Mycobacterium bovis/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Tuberculose Bovina/microbiologia , Reino Unido
15.
Epidemics ; 14: 26-35, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26972511

RESUMO

Mycobacterium bovis is the causal agent of bovine tuberculosis, one of the most important diseases currently facing the UK cattle industry. Here, we use high-density whole genome sequencing (WGS) in a defined sub-population of M. bovis in 145 cattle across 66 herd breakdowns to gain insights into local spread and persistence. We show that despite low divergence among isolates, WGS can in principle expose contributions of under-sampled host populations to M. bovis transmission. However, we demonstrate that in our data such a signal is due to molecular type switching, which had been previously undocumented for M. bovis. Isolates from farms with a known history of direct cattle movement between them did not show a statistical signal of higher genetic similarity. Despite an overall signal of genetic isolation by distance, genetic distances also showed no apparent relationship with spatial distance among affected farms over distances <5 km. Using simulations, we find that even over the brief evolutionary timescale covered by our data, Bayesian phylogeographic approaches are feasible. Applying such approaches showed that M. bovis dispersal in this system is heterogeneous but slow overall, averaging 2 km/year. These results confirm that widespread application of WGS to M. bovis will bring novel and important insights into the dynamics of M. bovis spread and persistence, but that the current questions most pertinent to control will be best addressed using approaches that more directly integrate WGS with additional epidemiological data.


Assuntos
Mycobacterium bovis/genética , Tuberculose Bovina/genética , Tuberculose Bovina/transmissão , Animais , Teorema de Bayes , Bovinos , Estudo de Associação Genômica Ampla
16.
J Vet Med Sci ; 78(5): 727-32, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26876219

RESUMO

Many studies suggest significant genetic variation in the resistance of cattle and humans to infection with Mycobacterium bovis (M. bovis), the causative agent of zoonotic tuberculosis. TNF-α promotes inflammation and induces apoptosis in response to mycobacterial infection. The aim of the present study was to investigate the influence of single nucleotide polymorphisms of the TNF-α gene on bovine tuberculosis (bTB) susceptibility. We genotyped the TNF-α gene in 74 bTB-infected Holstein cows and 90 healthy control animals. The influence in the exon 3 region of TNF-α polymorphisms on bTB susceptibility was subsequently investigated by association analysis. Our finding demonstrated that the g.27534932A>C polymorphism of the TNF-α is associated with bTB in Holstein cattle. The susceptibility of cattle with the g.27534932A>C genotype compared with the CC genotype was 4.11-fold (95% CI, 1.27-13.36; P=0.02) higher. The g.27534932A>C polymorphism located in exon 3 of the TNF-α gene, and the functional consequence was missense. The deduced amino acid sequence for the protein product revealed an arginine to serine conversion at position 159, which may affect initiation of protein synthesis and disrupt normal TNF-α function that protects animals against mycobacterial infection. A significant association was observed with the A allele as a risk factor for bTB susceptibility (OR, 3.84; 95% CI, 1.21-12.17; P=0.02). In conclusion, this is the first report showing that the g.27534932A>C polymorphism may contribute to TNF-α-mediated bTB susceptibility.


Assuntos
Tuberculose Bovina/genética , Fator de Necrose Tumoral alfa/genética , Animais , Estudos de Casos e Controles , Bovinos , Feminino , Predisposição Genética para Doença/genética , Masculino , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fator de Necrose Tumoral alfa/fisiologia
18.
FEBS J ; 283(5): 776-90, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26782926

RESUMO

Bovine tuberculosis results from infection with Mycobacterium bovis, a member of the Mycobacterium tuberculosis family. Worldwide, M. bovis infections result in economic losses in the livestock industry; cattle production is especially hard-hit by this disease. Generating M. bovis-resistant cattle may potentially mitigate the impact of this disease by reducing M. bovis infections. In this study, we used transgenic somatic cell nuclear transfer to generate cattle expressing the gene encoding human ß-defensin 3 (HBD3), which confers resistance to mycobacteria in vitro. We first generated alveolar epithelial cells expressing HBD3 under the control of the bovine MUC1 promoter, and confirmed that these cells secreted HBD3 and possessed anti-mycobacterial capacity. We then generated and identified transgenic cattle by somatic cell nuclear transfer. The cleavage and blastocyst formation rates of genetically modified embryos provided evidence that monoclonal transgenic bovine fetal fibroblast cells have an integral reprogramming ability that is similar to that of normal cells. Five genetically modified cows were generated, and their anti-mycobacterial capacities were evaluated. Alveolar epithelial cells and macrophages from these cattle expressed higher levels of HBD3 protein compared with non-transgenic cells and possessed effective anti-mycobacterial capacity. These results suggest that the overall risk of M. bovis infection in transgenic cattle is efficiently reduced, and support the development of genetically modified animals as an effective tool to reduce M. bovis infection.


Assuntos
Animais Geneticamente Modificados , Bovinos/genética , Tuberculose Bovina/genética , Tuberculose Bovina/prevenção & controle , beta-Defensinas/genética , Animais , Blastocisto/citologia , Células Epiteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Macrófagos/metabolismo , Mycobacterium bovis , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Alvéolos Pulmonares/citologia , Reação em Cadeia da Polimerase em Tempo Real , Distribuição Tecidual , Transgenes , beta-Defensinas/biossíntese
19.
J Vet Med Sci ; 78(2): 281-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26468216

RESUMO

Many studies suggest significant genetic variation in the resistance of cattle and humans to infection with Mycobacterium bovis, the causative agent of zoonotic tuberculosis. The inducible nitric oxide synthase (iNOS which is encoded by the NOS2 gene) plays a key role in the immunological control of a broad spectrum of infectious agents. This study aimed to investigate the influence of genetic variations in the promoter of the NOS2 gene on bovine tuberculosis (bTB) susceptibility. In this study, the NOS2 genes of 74 bTB-infected Holstein cows and 90 healthy controls were genotyped using PCR followed by nucleotide sequencing. Polymorphisms at rs207692718, rs109279434, rs209895548, rs385993919, rs433717754, rs383366213, rs466730386, rs715225976, rs525673647, rs720757654 and g.19958101T>G in the promoter region of the NOS2 gene were detected. The g.19958101T>G SNP produced two different conformation patterns (TT and TG) and the TG genotype was over-represented in the bTB group (20.27%) compared with the control group (2.22%). The TG genotype frequency of the g.19958101T>G variant was significantly higher in bTB cattle than in healthy controls (OR, 11.19; 95% CI, 2.47-50.73; P=0.0002). The G allele of the g.19958101T>G polymorphism was more frequent in bTB group when compared to control group (10.14% versus 1.11%). Furthermore, the G allele was a risk factor for bTB susceptibility (OR, 10.04; 95% CI, 2.26-44.65; P=0.0002). In conclusion, the g.19958101T>G polymorphism of the NOS2 gene may contribute to the susceptibility of Holstein cattle to bTB.


Assuntos
Óxido Nítrico Sintase Tipo II/genética , Tuberculose Bovina/genética , Animais , Bovinos , Feminino , Masculino , Reação em Cadeia da Polimerase/veterinária , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Fatores de Risco
20.
Microb Pathog ; 93: 78-82, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26657720

RESUMO

Apoptosis was considered as one of the important host defense mechanisms against mycobacteria infection. In macrophage, the main target cell of Mycobacterium tuberculosis, apoptosis after infection could help kill the bacillus inside and process the antigens for further presentation and proper immune response. Here, we identified a role of TLR8 during the apoptosis induced by Bacillus Calmette Guérin (BCG) infection in THP-1 cells. Knockdown TLR8 further increased the apoptosis induced by BCG infection, and this enhanced apoptosis was caspase-dependent. During this process, Erk1/2, JNK and NFκB pathways were negatively affected and contributed to the enhanced apoptosis.


Assuntos
Apoptose , Macrófagos/citologia , Mycobacterium bovis/fisiologia , Receptor 1 Toll-Like/metabolismo , Tuberculose Bovina/metabolismo , Tuberculose Bovina/fisiopatologia , Animais , Bovinos , Linhagem Celular , Macrófagos/metabolismo , Macrófagos/microbiologia , Mycobacterium bovis/genética , Transdução de Sinais , Receptor 1 Toll-Like/genética , Tuberculose Bovina/genética , Tuberculose Bovina/microbiologia
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