Now showing 1 - 10 of 11
  • Publication
    Computational selection of novel antigenic targets in the Mycobacterium bovis proteome
    The discovery of novel antigens is an essential requirement in devising new diagnostics for use in both M. tuberculosis (Mtb) and M. bovis control programmes. Reverse vaccinology is now a feasible method of extracting potential immunogenic epitopes from bacterial genomes to reduce the cost of experimental screening of antigens for anamnestic responses in infected hosts. Since a significant focus has been on the role of CD4+ T cells, the ability to predict peptide binding to MHC-II molecules is seen as a key step in discovery.Previous antigen-mining experiments for identification of novel diagnostic or vaccine candidates for human and bovine TB follow a targeted approach, where specific groups of proteins suspected to contain likely candidates are identified and evaluated for  mmunogenicity. A disadvantage of those approaches is that they are restricted to a relatively small set of proteins biased by the initial selection criteria. Our objective was to computationally select antigens in a less biased manner.
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  • Publication
    A Point Mutation in cycA Partially Contributes to the D-cycloserine Resistance Trait of Mycobacterium bovis BCG Vaccine Strains
    In mycobacteria, CycA a D-serine, L- and D-alanine, and glycine transporter also functions in the uptake of D-cycloserine, an important second-line anti-tubercular drug. A single nucleotide polymorphism identified in the cycA gene of BCG was hypothesized to contribute to the increased resistance of Mycobacterium bovis bacillus Calmette-Guérin (BCG) to D-cycloserine compared to wild-type Mycobacterium tuberculosis or Mycobacterium bovis. Working along these lines, a merodiploid strain of BCG expressing Mycobacterium tuberculosis CycA was generated and found to exhibit increased susceptibility to D-cycloserine albeit not to the same extent as wild-type Mycobacterium tuberculosis or Mycobacterium bovis. In addition, recombinant Mycobacterium smegmatis strains expressing either Mycobacterium tuberculosis or Mycobacterium bovis CycA but not BCG CycA were rendered more susceptible to D-cycloserine. These findings support the notion that CycA-mediated uptake in BCG is impaired as a result of a single nucleotide polymorphism; however, the partial contribution of this impairment to D-cycloserine resistance suggests the involvement of additional genetic lesions in this phenotype.
      826Scopus© Citations 46
  • Publication
    Genome-level analyses of Mycobacterium bovis lineages reveal the role of SNPs and antisense transcription in differential gene expression
    Bovine tuberculosis (bTB) is a disease with major implications for animal welfare and productivity, as well as having the potential for zoonotic transmission. In Great Britain (GB) alone, controlling bTB costs in the region of £100 million annually, with the current control scheme seemingly unable to stop the inexorable spread of infection. One aspect that may be driving the epidemic is evolution of the causative pathogen, Mycobacterium bovis. To understand the underlying genetic changes that may be responsible for this evolution, we performed a comprehensive genome-level analyses of 4 M. bovis strains that encompass the main molecular types of the pathogen circulating in GB.
      447Scopus© Citations 23
  • Publication
    GOexpress: an R/Bioconductor package for the identification and visualisation of robust gene ontology signatures through supervised learning of gene expression data
    Background: Identification of gene expression profiles that differentiate experimental groups is critical for discovery and analysis of key molecular pathways and also for selection of robust diagnostic or prognostic biomarkers. While integration of differential expression statistics has been used to refine gene set enrichment analyses, such approaches are typically limited to single gene lists resulting from simple two-group comparisons or time-series analyses. In contrast, functional class scoring and machine learning approaches provide powerful alternative methods to leverage molecular measurements for pathway analyses, and to compare continuous and multi-level categorical factors. Results: We introduce GOexpress, a software package for scoring and summarising the capacity of gene ontology features to simultaneously classify samples from multiple experimental groups. GOexpress integrates normalised gene expression data (e.g., from microarray and RNA-seq experiments) and phenotypic information of individual samples with gene ontology annotations to derive a ranking of genes and gene ontology terms using a supervised learning approach. The default random forest algorithm allows interactions between all experimental factors, and competitive scoring of expressed genes to evaluate their relative importance in classifying predefined groups of samples. Conclusions: GOexpress enables rapid identification and visualisation of ontology-related gene panels that robustly classify groups of samples and supports both categorical (e.g., infection status, treatment) and continuous (e.g., time-series, drug concentrations) experimental factors. The use of standard Bioconductor extension packages and publicly available gene ontology annotations facilitates straightforward integration of GOexpress within existing computational biology pipelines.
      738Scopus© Citations 21
  • Publication
    Agricultural anaerobic digestion power plants in Ireland and Germany: policy & practice
    The process of anaerobic digestion (AD) is valued as a carbon-neutral energy source, while simultaneously treating organic waste, making it safer for disposal or use as a fertilizer on agricultural land. The AD process in many European nations, such as Germany, has grown from use of small, localized digesters to the operation of large-scale treatment facilities, which contribute significantly to national renewable energy quotas. However, these large AD plants are costly to run and demand intensive farming of energy crops for feedstock. Current policy in Germany has transitioned to support funding for smaller digesters, while also limiting the use of energy crops. AD within Ireland, as a new technology, is affected by ambiguous governmental policies concerning waste and energy. A clear governmental strategy supporting on-site AD processing of agricultural waste will significantly reduce Ireland's carbon footprint, improve the safety and bioavailability of agricultural waste, and provide an indigenous renewable energy source.
      1619Scopus© Citations 23
  • Publication
    Characterisation of the transcriptional regulator Rv3124 of Mycobacterium tuberculosis identifies it as a positive regulator of molybdopterin biosynthesis and defines the functional consequences of a nonsynonymous SNP in the Mycobacterium bovis BCG orthologue
    A number of single nucleotide polymorphisms (SNPs) have been identified in the genome of Mycobacterium bovis BCG Pasteur compared to the sequenced strain M. bovis 2122/97. The functional consequences of many of these mutations remain to be described; however mutations in genes encoding regulators may be particularly relevant to global phenotypic changes such as loss of virulence, since alteration of a regulator's function will affect the expression of a wide range of genes. One such SNP falls in bcg3145, encoding a member of the AfsR/DnrI/SARP class of global transcriptional regulators, and replaces with glycine a highly conserved glutamic acid residue at position 159 (E159G) in a tetratricopeptide repeat (TPR) located in the bacterial transcriptional activation (BTA) domain of BCG3145. TPR domains are associated with protein-protein interactions, and a conserved core (helices T1-T7) of the BTA domain seems to be required for proper function of SARP-family proteins. Structural modelling predicted that the E159G mutation perturbs the third a-helix of the BTA domain and could therefore have functional consequences. The E159G SNP was found to be present in all BCG strains, but absent from virulent M. bovis and M. tuberculosis strains. By overexpressing BCG3145 and Rv3124 in BCG and H37Rv and monitoring transcriptome changes using microarrays, we determined that BCG3145/Rv3124 acts as a positive transcriptional regulator of the molybdopterin biosynthesis moa1 operon, and suggest that rv3124 be renamed moaR1. The SNP in bcg3145 was found to have a subtle effect on the activity of MoaR1, suggesting that this mutation is not a key event in the attenuation of BCG..
      325Scopus© Citations 15
  • Publication
    Database resources for the tuberculosis community
    Access to online repositories for genomic and associated "-omics" datasets is now an essential part of everyday research activity. It is important therefore that the Tuberculosis community is aware of the databases and tools available to them online, as well as for the database hosts to know what the needs of the research community are. One of the goals of the Tuberculosis Annotation Jamboree, held in Washington DC on March 7th-8th 2012, was therefore to provide an overview of the current status of three key Tuberculosis resources, TubercuList (tuberculist.epfl.ch), TB Database (www.tbdb.org), and Pathosystems Resource Integration Center (PATRIC, www.patricbrc.org). Here we summarize some key updates and upcoming features in TubercuList, and provide an overview of the PATRIC site and its online tools for pathogen RNA-Seq analysis.
      443Scopus© Citations 24
  • Publication
    Comparative Mycobacteriology of the Mycobacterium tuberculosis complex
    (CAB International, 2015) ;
    The Mycobacterium tuberculosis complex (MTBC) is a group of highly genetically related pathogens that cause tuberculosis (TB) in mammalian species. However, the very name of the complex underlines the fact that our knowledge of these pathogens is dominated by studies on the human pathogen, M. tuberculosis. Of course this is entirely justified; M. tuberculosis is a major global pathogen that exacts a horrendous burden in terms of mortality and morbidity so it is appropriate that it is the cornerstone of the complex. In the same way as M. tuberculosis is the best studied human tubercle bacillus, our knowledge of the animal-adapted strains has been dominated by studies with M. bovis. Again, given the economic importance of bovine TB and the potential for zoonotic transmission to humans, this is entirely expected. However, taking M. tuberculosis and M. bovis as the human- and animal-adapted poles¿of the complex, our focus on these pathogens to the exclusion of others members has restricted, and potentially skewed, our understanding of diversity, virulence and host adaptation within the MTBC. Referring to Theobald Smith above, have we really exploited comparative studies of the tubercle bacilli to their full potential, or have we regarded the MTBC as merely M. tuberculosis plus some animal pathogens of lesser import? Herein we discuss our current understanding of the make-up of the MTBC, focussing on comparisons of M. tuberculosis and M. bovis as the exemplar human- and animal-adapted strains, and look to what studies of these pathogens can teach us about the evolution of the MTBC specifically and the emergence of host adaptation in pathogens in general. We also speculate on how our current focus on M. tuberculosis and M. bovis may have hindered our appreciation of fundamental concepts such as virulence, evolution and host adaptation of the tubercle bacilli.
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  • Publication
    Tuberculosis 2012: biology, pathogenesis and intervention strategies; an update from the city of light
    Tuberculosis (TB) remains one of the world's most deadly infectious diseases, with approximately 1.5 million deaths and 9 million new cases of TB in 2010. There is an urgent global need to develop new control tools, with advances necessary in our basic understanding of the pathogen, Mycobacterium tuberculosis, and translation of these findings to public health. It was in this context that the "Tuberculosis 2012: Biology, Pathogenesis, Intervention Strategies" meeting was held in the Institut Pasteur, Paris, France from 11 to 15th Sept 2012. The meeting brought together over 600 delegates from across the globe to hear updates on the latest research findings and how they are underpinning the development of novel vaccines, diagnostics, and drugs.
      745Scopus© Citations 5
  • Publication
    Advancing national animal health and welfare policy
    The University College Dublin (UCD) School of Veterinary Medicine has a broad research agenda covering areas such as veterinary public health, epidemiology and national disease control, herd health management, drug delivery, pharmacology, parasitology, and One Health research. We work with national and international collaborators and, with the support of Zoetis, have a longstanding “UCD Squared” partnership with the University of California-Davis, which has established an ambitious program of research, drawing on expertise from a diverse community of veterinary and medical scientists and clinicians.
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