Systems Biology-Derived Genetic Signatures of Mastitis in Dairy Cattle: A New Avenue for Drug Repurposing.
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ABSTRACT:
SUBMITTER: Sharifi S
PROVIDER: S-EPMC8749881 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Mastitis is the most prevalent disease in dairy cattle and one of the most significant bovine pathologies affecting milk production, animal health, and reproduction. In addition, mastitis is the most common, expensive, and contagious infection in the dairy industry. Methods: A meta-analysis of microarray and RNA-seq data was conducted to identify candidate genes and functional modules associated with mastitis disease. The results were then applied to systems biology analysis via weighted gene coexpression network analysis (WGCNA), Gene Ontology, enrichment analysis for the Kyoto Encyclopedia of Genes and Genomes (KEGG), and modeling using machine-learning algorithms. Results: Microarray and RNA-seq datasets were generated for 2,089 and 2,794 meta-genes, respectively. Between microarray and RNA-seq datasets, a total of 360 meta-genes were found that were significantly enriched as "peroxisome," "NOD-like receptor signaling pathway," "IL-17 signaling pathway," and "TNF signaling pathway" KEGG pathways. The turquoise module (n = 214 genes) and the brown module (n = 57 genes) were identified as critical functional modules associated with mastitis through WGCNA. PRDX5, RAB5C, ACTN4, SLC25A16, MAPK6, CD53, NCKAP1L, ARHGEF2, COL9A1, and PTPRC genes were detected as hub genes in identified functional modules. Finally, using attribute weighting and machine-learning methods, hub genes that are sufficiently informative in Escherichia coli mastitis were used to optimize predictive models. The constructed model proposed the optimal approach for the meta-genes and validated several high-ranked genes as biomarkers for E. coli mastitis using the decision tree (DT) method. Conclusion: The candidate genes and pathways proposed in this study may shed new light on the underlying molecular mechanisms of mastitis disease and suggest new approaches for diagnosing and treating E. coli mastitis in dairy cattle.
| S-EPMC8531812 | biostudies-literature
Project description:Motivation:Identification of novel therapeutic effects for existing US Food and Drug Administration (FDA)-approved drugs, drug repurposing, is an approach aimed to dramatically shorten the drug discovery process, which is costly, slow and risky. Several computational approaches use transcriptional data to find potential repurposing candidates. The main hypothesis of such approaches is that if gene expression signature of a particular drug is opposite to the gene expression signature of a disease, that drug may have a potential therapeutic effect on the disease. However, this may not be optimal since it fails to consider the different roles of genes and their dependencies at the system level. Results:We propose a systems biology approach to discover novel therapeutic roles for established drugs that addresses some of the issues in the current approaches. To do so, we use publicly available drug and disease data to build a drug-disease network by considering all interactions between drug targets and disease-related genes in the context of all known signaling pathways. This network is integrated with gene-expression measurements to identify drugs with new desired therapeutic effects based on a system-level analysis method. We compare the proposed approach with the drug repurposing approach proposed by Sirota et al. on four human diseases: idiopathic pulmonary fibrosis, non-small cell lung cancer, prostate cancer and breast cancer. We evaluate the proposed approach based on its ability to re-discover drugs that are already FDA-approved for a given disease. Availability and implementation:The R package DrugDiseaseNet is under review for publication in Bioconductor and is available at https://github.com/azampvd/DrugDiseaseNet. Supplementary information:Supplementary data are available at Bioinformatics online.
| S-EPMC6084573 | biostudies-literature
Project description:Japanese encephalitis is a zoonotic disease caused by the Japanese encephalitis virus (JEV). It is mainly epidemic in Asia with an estimated 69,000 cases occurring per year. However, no approved agents are available for the treatment of JEV infection, and existing vaccines cannot control various types of JEV strains. Drug repurposing is a new concept for finding new indication of existing drugs, and, recently, the concept has been used to discover new antiviral agents. Identifying host proteins involved in the progress of JEV infection and using these proteins as targets are the center of drug repurposing for JEV infection. In this study, based on the gene expression data of JEV infection and the phenome-wide association study (PheWAS) data, we identified 286 genes that participate in the progress of JEV infection using systems biology methods. The enrichment analysis of these genes suggested that the genes identified by our methods were predominantly related to viral infection pathways and immune response-related pathways. We found that bortezomib, which can target these genes, may have an effect on the treatment of JEV infection. Subsequently, we evaluated the antiviral activity of bortezomib using a JEV-infected mouse model. The results showed that bortezomib can lower JEV-induced lethality in mice, alleviate suffering in JEV-infected mice and reduce the damage in brains caused by JEV infection. This work provides an agent with new indication to treat JEV infection.
| S-EPMC6320907 | biostudies-literature
Project description:Obstetric diseases remain underserved and understudied. Drug repurposing-utilization of a drug whose use is accepted in one condition for a different condition-could represent a rapid and low-cost way to identify new therapies that are known to be safe. In diseases of pregnancy, the known safety profile is a strong additional incentive. We describe the techniques and steps used in the use of 'omics data for drug repurposing. We illustrate these techniques using case studies of published drug repurposing projects. We provide a set of available databases with low barriers to entry which investigators can use to perform their own projects. The promise of 'omics techniques is unbiased screening, either of all drug targets or of all patients using particular drugs to find which are likely to alter disease risk or progression. However, we caution that reproducibility across the underlying studies, and thus the drugs suggested for repurposing, can be poor. We suggest that improved nosology, for example correlating patient clinical conditions with placental pathology, could yield more robust associations. We conclude that 'omics-driven drug repurposing represents a potential fruitful path to discover new, safe treatments of obstetric diseases.
| S-EPMC6105384 | biostudies-literature
Project description:BACKGROUND: One major problem in dairy cattle husbandry is the prevalence of udder infections. In today's breeding programmes, top priority is being given to making animal evaluation more cost-effective and reliable and less time-consuming. We proposed tumor necrosis factor ? (TNF-?), lactoferrin (LTF) and macrophage-expressed lysozyme (mLYZ) genes as potential DNA markers in the improvement of immunity to mastitis.This study included 588 Polish Holstein-Friesian cows kept on one farm located in the north-western region of Poland. All clinical cases of mastitis in the herd under study were recorded by a qualified veterinarian employed by the farm. The following indicators were applied to determine udder immunity to mastitis in the cows under study: morbidity rate (MR), duration of mastitis (DM) and extent of mastitis (EM). TNF-?, mLYZ and LTF genotypes were identified by real-time PCR method, using SimpleProbe technology. Due to the very low frequency of mLYZ allele T, the gene was excluded from further analysis.A statistical analysis of associations between TNF-? and LTF genes and immunity to mastitis were performed using three models: 1) a parity-averaged model including only additive effects of the genes; 2) a parity-averaged model including both additive and epistatic effects of the genes; and 3) a parity-specific model including only additive effects of the genes. RESULTS: With the first and second models it was revealed that the genes effects on the applied indicators of immunity to mastitis were non-significant whereas with the third one the effects were found to be statistically significant. Particularly noteworthy was the finding that the effects of TNF-? and LTF varied depending on age (parity). The alleles which were linked to high immunity to mastitis in lower parities appeared to be less favourable in higher parities. CONCLUSIONS: These interactions might be related to inflamm-ageing, that is an increased susceptibility to infection due to immune system deregulation that progresses with age. Such pattern of interactions makes it impossible to use the genes in question in marker-assisted selection aimed at reducing heritable susceptibility to mastitis. This is because the immune mechanisms behind resistance to infections proved to be too complex.
| S-EPMC3682883 | biostudies-other
Project description:The innate immune response plays an important role in the course of bacterial infections. Innate immunity effectiveness relies on the expression of many genes, connected, among others, to the activity of neutrophils. Interleukin 8 (IL-8) receptor ?, coded by the CXCR1 gene, is present on the neutrophil surface and binds pro-inflammatory IL-8 with high affinity. This is why the bovine CXCR1 gene carries a potential for use as a dairy cattle mastitis marker. To date, several studies on the CXCR1 polymorphism brought out contradictory results. The aim of this study was to analyse the association between two SNPs of the CXCR1 gene, which is potentially important for the protein function and animal phenotype for mastitis susceptibility. A total of 554 Polish Holsteins were genotyped, and 140 among them were bacteriologically tested. The differences between animals carrying different genotypes and haplotypes of CXCR1 in test day somatic cell count (SCC) and Staphylococcus aureus mastitis susceptibility were estimated. We found that test day SCC was significantly related to CXCR1+472 SNP but not to CXCR1+735 SNP. No statistically significant association between CXCR1 polymorphism and susceptibility to S. aureus mastitis was found in the studied herd.
| S-EPMC4637389 | biostudies-literature
Project description:BackgroundInflammation of the mammary tissue (mastitis) is one of the most detrimental health conditions in dairy ruminants and is considered the most economically important infectious disease of the dairy sector. Improving mastitis resistance is becoming an important goal in dairy ruminant breeding programmes. However, mastitis resistance is a complex trait and identification of mastitis-associated alleles in livestock is difficult. Currently, the only applicable approach to identify candidate loci for complex traits in large farm animals is to combine different information that supports the functionality of the identified genomic regions with respect to a complex trait.MethodsTo identify the most promising candidate loci for mastitis resistance we integrated heterogeneous data from multiple sources and compiled the information into a comprehensive database of mastitis-associated candidate loci. Mastitis-associated candidate genes reported in association, expression, and mouse model studies were collected by searching the relevant literature and databases. The collected data were integrated into a single database, screened for overlaps, and used for gene set enrichment analysis.ResultsThe database contains candidate genes from association and expression studies and relevant transgenic mouse models. The 2448 collected candidate loci are evenly distributed across bovine chromosomes. Data integration and analysis revealed overlaps between different studies and/or with mastitis-associated QTL, revealing promising candidate genes for mastitis resistance.ConclusionMastitis resistance is a complex trait influenced by numerous alleles. Based on the number of independent studies, we were able to prioritise candidate genes and propose a list of the 22 most promising. To our knowledge this is the most comprehensive database of mastitis associated candidate genes and could be helpful in selecting genes for functional validation studies.
| S-EPMC9912691 | biostudies-literature
Project description:Multiple studies have investigated selection signatures in domestic cattle and other species. However, there is a dearth of information about the response to selection in genomes of highly admixed crossbred cattle in relation to production and adaptation to tropical environments. In this study, we evaluated 839 admixed crossbred cows sampled from two major dairy regions in Tanzania namely Rungwe and Lushoto districts, in order to understand their genetic architecture and detect genomic regions showing preferential selection. Animals were genotyped at 150,000 SNP loci using the Geneseek Genomic Profiler (GGP) High Density (HD) SNP array. Population structure analysis showed a large within-population genetic diversity in the study animals with a high degree of variation in admixture ranging between 7 and 100% taurine genes (dairyness) of mostly Holstein and Friesian ancestry. We explored evidence of selection signatures using three statistical methods (iHS, XP-EHH, and pcadapt). Selection signature analysis identified 108 candidate selection regions in the study population. Annotation of these regions yielded interesting genes potentially under strong positive selection including ABCG2, ABCC2, XKR4, LYN, TGS1, TOX, HERC6, KIT, PLAG1, CHCHD7, NCAPG, and LCORL that are involved in multiple biological pathways underlying production and adaptation processes. Several candidate selection regions showed an excess of African taurine ancestral allele dosage. Our results provide further useful insight into potential selective sweeps in the genome of admixed cattle with possible adaptive and productive importance. Further investigations will be necessary to better characterize these candidate regions with respect to their functional significance to tropical adaptations for dairy cattle.
| S-EPMC6305962 | biostudies-literature
Project description:This study described the occurrence of clinical and subclinical forms of mastitis in 250 cattle from 5 dairy farms around the cities of Santa Rosa and Machala, El Oro Province, Ecuador. Clinical mastitis (CM) was determined based on obvious changes in milk (mild), signs of inflammation in the udder (moderate), and/or generalized clinical symptoms (severe). Subclinical mastitis (SCM) was assessed using the California mastitis test. CM and SCM were detected in 30 (12.0%) and 150 (60%) of the 250 tested cattle, respectively. Prevalence at the udder quarter level was 57.7% (577/1,000), which was higher among forequarters (369/577; 63.9%) than hindquarters. Of the 577 mastitic milk samples subjected to microbiological analysis, 35 were excluded due to contamination and 20 tested negative. Identification of bacterial isolates revealed that 33.3% of the 93 CM samples contained coliforms, 25.8% coagulase-positive staphylococci, 20.4% coagulase-negative staphylococci (CNS), 9.7% streptococci, 7.5% Bacillus spp., and 3.2% Klebsiella spp. Bacterial profiling of the 429 SCM milk samples showed that 55.4% contained CNS, 22.1% Bacillus spp., 9.3% streptococci, and 6.1% coagulase-positive staphylococci. In vitro antibiotic susceptibility testing of the obtained isolates indicated that all were susceptible to amoxicillin, ampicillin, cefotaxime, enrofloxacin, sulfamethoxazole-trimethoprim, gentamicin, and neomycin. No multidrug-resistant strains were observed.
| S-EPMC6021881 | biostudies-literature
Project description:BackgroundSubclinical intramammary infection (IMI) represents a significant problem in maintaining dairy cows' health. Disease severity and extent depend on the interaction between the causative agent, environment, and host. To investigate the molecular mechanisms behind the host immune response, we used RNA-Seq for the milk somatic cells (SC) transcriptome profiling in healthy cows (n = 9), and cows naturally affected by subclinical IMI from Prototheca spp. (n = 11) and Streptococcus agalactiae (S. agalactiae; n = 11). Data Integration Analysis for Biomarker discovery using Latent Components (DIABLO) was used to integrate transcriptomic data and host phenotypic traits related to milk composition, SC composition, and udder health to identify hub variables for subclinical IMI detection.ResultsA total of 1,682 and 2,427 differentially expressed genes (DEGs) were identified when comparing Prototheca spp. and S. agalactiae to healthy animals, respectively. Pathogen-specific pathway analyses evidenced that Prototheca's infection upregulated antigen processing and lymphocyte proliferation pathways while S. agalactiae induced a reduction of energy-related pathways like the tricarboxylic acid cycle, and carbohydrate and lipid metabolism. The integrative analysis of commonly shared DEGs between the two pathogens (n = 681) referred to the core-mastitis response genes, and phenotypic data evidenced a strong covariation between those genes and the flow cytometry immune cells (r2 = 0.72), followed by the udder health (r2 = 0.64) and milk quality parameters (r2 = 0.64). Variables with r ≥ 0.90 were used to build a network in which the top 20 hub variables were identified with the Cytoscape cytohubba plug-in. The genes in common between DIABLO and cytohubba (n = 10) were submitted to a ROC analysis which showed they had excellent predictive performances in terms of discriminating healthy and mastitis-affected animals (sensitivity > 0.89, specificity > 0.81, accuracy > 0.87, and precision > 0.69). Among these genes, CIITA could play a key role in regulating the animals' response to subclinical IMI.ConclusionsDespite some differences in the enriched pathways, the two mastitis-causing pathogens seemed to induce a shared host immune-transcriptomic response. The hub variables identified with the integrative approach might be included in screening and diagnostic tools for subclinical IMI detection.
| S-EPMC10320993 | biostudies-literature