Dataset Information

Pathways and Genes Associated with Immune Dysfunction in Sheep Paratuberculosis.

ABSTRACT: Multibacillary and paucibacillary paratuberculosis are both caused by Mycobacterium avium subspecies paratuberculosis. Multibacillary lesions are composed largely of infected epithelioid macrophages and paucibacillary lesions contain T cells but few bacteria. Multibacillary disease is similar to human lepromatous leprosy, with variable/high levels of antibody and a dysfunctional immune response. Animals with paucibacillary disease have high cell-mediated immunity and variable levels of antibody. This study aims to characterize the immunological dysfunction using TruSeq analysis of the ileocaecal lymph node that drains disease lesions. Immune dysfunction is highlighted by repression of TCR/CD3 genes, T cell co-receptors/co-stimulators, T cell activation and signal-transduction genes. Inflammation was an acute phase response and chronic inflammation, with little evidence of acute inflammation. The high levels of immunoglobulin and plasma cell transcripts is consistent with the anti-MAP antibody responses in paratuberculosis sheep. Also notable was the overwhelming reduction in mast cell transcripts, potentially affecting DC activation of the immune response. This study also shows that there were no fundamental differences in the gene expression patterns in multibacillary and paucibacillary disease, no shift in T cell genes from Th1 to Th2 pattern but rather an incremental decline into immune dysfunction leading to multibacillary pathology.

SUBMITTER: Gossner A

PROVIDER: S-EPMC5402263 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pathways and Genes Associated with Immune Dysfunction in Sheep Paratuberculosis.

Gossner Anton A Watkins Craig C Chianini Francesca F Hopkins John J

Scientific reports 20170424

Multibacillary and paucibacillary paratuberculosis are both caused by Mycobacterium avium subspecies paratuberculosis. Multibacillary lesions are composed largely of infected epithelioid macrophages and paucibacillary lesions contain T cells but few bacteria. Multibacillary disease is similar to human lepromatous leprosy, with variable/high levels of antibody and a dysfunctional immune response. Animals with paucibacillary disease have high cell-mediated immunity and variable levels of antibody. ...[more]

PMID: 28436433

Similar Datasets

Project description:Mycoplasma ovipneumoniae contributes to polymicrobial pneumonia in domestic sheep. Elucidation of host genetic influences of M. ovipneumoniae nasal detection has the potential to reduce the incidence of polymicrobial pneumonia in sheep through implementation of selective breeding strategies. Nasal mucosal secretions were collected from 647 sheep from a large US sheep flock. Ewes of three breeds (Polypay n = 222, Rambouillet n = 321, and Suffolk n = 104) ranging in age from one to seven years, were sampled at three different times in the production cycle (February, April, and September/October) over four years (2015 to 2018). The presence and DNA copy number of M. ovipneumoniae was determined using a newly developed species-specific qPCR. Breed (P<0.001), age (P<0.024), sampling time (P<0.001), and year (P<0.001) of collection affected log10 transformed M. ovipneumoniae DNA copy number, where Rambouillet had the lowest (P<0.0001) compared with both Polypay and Suffolk demonstrating a possible genetic component to detection. Samples from yearlings, April, and 2018 had the highest (P<0.046) detected DNA copy number mean. Sheep genomic DNA was genotyped with the Illumina OvineHD BeadChip. Principal component analysis identified most of the variation in the dataset was associated with breed. Therefore, genome wide association analysis was conducted with a mixed model (EMMAX), with principal components 1 to 6 as fixed and a kinship matrix as random effects. Genome-wide significant (P<9x10-8) SNPs were identified on chromosomes 6 and 7 in the all-breed analysis. Individual breed analysis had genome-wide significant (P<9x10-8) SNPs on chromosomes 3, 4, 7, 9, 10, 15, 17, and 22. Annotated genes near these SNPs are part of immune (ANAPC7, CUL5, TMEM229B, PTPN13), gene translation (PIWIL4), and chromatin organization (KDM2B) pathways. Immune genes are expected to have increased expression when leukocytes encounter M. ovipneumoniae which would lead to chromatin reorganization. Work is underway to narrow the range of these associated regions to identify the underlying causal mutations.

Project description:Multiple organ dysfunction syndrome (MODS) is characterized by the development of progressive physiological dysfunction of ?2 organs or organ systems and is responsible for the majority of the morbidity and mortality among patients in intensive care units. The aim of the present study was to investigate the potential genes and pathways associated with MODS. The microarray dataset GSE60088 was downloaded from the Gene Expression Omnibus and used to identify differentially expressed genes (DEGs) between organ tissues (lung, liver and kidney) obtained from a murine model of MODS and healthy controls. The interactions between DEGs in lungs, liver and kidneys were revealed by Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, protein?protein interaction (PPI) data for DEGs were obtained from the Search Tool for the Retrieval of Interacting Genes and a PPI network was constructed. Additionally, DEGs that were common among the three organs were screened and transcription factors that regulated them were predicted using the iRegulon plugin. A total of 943, 267 and 227 DEGs were identified in lung, liver and kidney samples, respectively, between mice with MODS and healthy controls. In lung and liver samples, two pathways that were enriched with DEGs were identified and were common between lung and liver samples, including 'cytokine?cytokine receptor interaction' and 'Jnk?STAT signaling pathway', and examples of DEGs associated with these pathways include C?X?C motif chemokine ligand (Cxcl)1 and Cxcl10, and signal transducer and activator of transcription (Stat)1, respectively. Furthermore, two common pathways were identified in liver and kidney samples, which included 'MAPK signaling pathway' and 'p53 signaling pathway', and DEGs associated with these pathways included growth arrest and DNA damage?inducible ?. A total of 18 DEGs were common among lung, liver and kidney tissues, including CCAAT/enhancer binding protein ? (Cebpb) and olfactomedin?like 1 (Olfml1). Cebpb modulated various other DEGs, such as Cxcl1, and Olfml1 was regulated by Stat5A. These genes and pathways may serve roles in the progression of MODS and may be considered to be potential therapy targets for MODS.

Project description:PurposeTo select individuals and families with a low genetic burden for age-related macular degeneration (AMD), to inform the clinical diagnosis of macular disorders, and to find novel genetic variants associated with maculopathies.DesignGenetic association study based on targeted and whole-exome sequencing.ParticipantsA total of 758 subjects (481 individuals with maculopathy and 277 controls), including 316 individuals in 72 families.MethodsWe focused on 150 genes involved in the complement, coagulation, and inflammatory pathways. Single-variant tests were performed on 7755 variants shared among ≥ 5 subjects using logistic regression. Gene-based tests were used to evaluate aggregate effects from rare and low-frequency variants (at minor allele frequency [MAF] ≤ 5% or ≤ 1%) in a gene using burden tests. For families whose affected members had a low burden of genetic risk based on known common and rare variants related to AMD, we searched for rare variants (MAF < 0.001) whose risk alleles occurred in ≥ 80% of affected individuals but not in controls. Immunohistochemistry was performed to determine the protein expression of a novel gene (coagulation factor II thrombin receptor-like 2 [F2RL2]) in retinal tissues.Main outcome measuresGenotypes and phenotypes of macular degeneration.ResultsWe confirmed the association of a synonymous variant in complement factor H (Ala473, rs2274700, proxy to intronic rs1410996, r 2 = 1) with maculopathy (odds ratio, 0.64; P = 4.5 × 10-4). Higher AMD polygenic risk scores (PRSs) were associated with intermediate and advanced AMD. Among families with low PRSs and no known rare variants for maculopathy, we identified 2 novel, highly penetrant missense rare variants in ADAM15, A disintegrin and metalloprotease, metallopeptidase domain 15 (p.Arg288Cys) and F2RL2 (p.Leu289Arg). Immunohistochemistry analyses revealed F2RL2 protein expression in cone photoreceptor outer segments and Müller glia cells of human and pig retinas. Coagulation factor II thrombin receptor-like 2 expression appeared increased in fibrotic areas in advanced AMD samples with neovascularization, suggesting that F2RL2 may play a role in the progression to advanced macular disease.ConclusionsNew missense rare variants in the genes ADAM15 and F2RL2 were associated with maculopathies. Results suggest that novel genes related to the coagulation and immune pathways may be involved in the pathogenesis of macular diseases.

Dataset Information

Pathways and Genes Associated with Immune Dysfunction in Sheep Paratuberculosis.

Publications

Pathways and Genes Associated with Immune Dysfunction in Sheep Paratuberculosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets