Veterinary Biosciences - Research Publications

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    Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain
    Preston, S ; Korhonen, PK ; Mouchiroud, L ; Cornaglia, M ; McGee, SL ; Young, ND ; Davis, RA ; Crawford, S ; Nowell, C ; Ansell, BRE ; Fisher, GM ; Andrews, KT ; Chang, BCH ; Gijs, MAM ; Sternberg, PW ; Auwerx, J ; Baell, J ; Hofmann, A ; Jabbar, A ; Gasser, RB (WILEY, 2017-10-01)
    As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.
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    The genome and developmental transcriptome of the strongylid nematode Haemonchus contortus
    Schwarz, EM ; Korhonen, PK ; Campbell, BE ; Young, ND ; Jex, AR ; Jabbar, A ; Hall, RS ; Mondal, A ; Howe, AC ; Pell, J ; Hofmann, A ; Boag, PR ; Zhu, X-Q ; Gregory, TR ; Loukas, A ; Williams, BA ; Antoshechkin, I ; Brown, CT ; Sternberg, PW ; Gasser, RB (BMC, 2013-01-01)
    BACKGROUND: The barber's pole worm, Haemonchus contortus, is one of the most economically important parasites of small ruminants worldwide. Although this parasite can be controlled using anthelmintic drugs, resistance against most drugs in common use has become a widespread problem. We provide a draft of the genome and the transcriptomes of all key developmental stages of H. contortus to support biological and biotechnological research areas of this and related parasites. RESULTS: The draft genome of H. contortus is 320 Mb in size and encodes 23,610 protein-coding genes. On a fundamental level, we elucidate transcriptional alterations taking place throughout the life cycle, characterize the parasite's gene silencing machinery, and explore molecules involved in development, reproduction, host-parasite interactions, immunity, and disease. The secretome of H. contortus is particularly rich in peptidases linked to blood-feeding activity and interactions with host tissues, and a diverse array of molecules is involved in complex immune responses. On an applied level, we predict drug targets and identify vaccine molecules. CONCLUSIONS: The draft genome and developmental transcriptome of H. contortus provide a major resource to the scientific community for a wide range of genomic, genetic, proteomic, metabolomic, evolutionary, biological, ecological, and epidemiological investigations, and a solid foundation for biotechnological outcomes, including new anthelmintics, vaccines and diagnostic tests. This first draft genome of any strongylid nematode paves the way for a rapid acceleration in our understanding of a wide range of socioeconomically important parasites of one of the largest nematode orders.
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    Proteomic Analysis of Oesophagostomum dentatum (Nematoda) during Larval Transition, and the Effects of Hydrolase Inhibitors on Development
    Ondrovics, M ; Silbermayr, K ; Mitreva, M ; Young, ND ; Razzazi-Fazeli, E ; Gasser, RB ; Joachim, A ; Hofmann, A (PUBLIC LIBRARY SCIENCE, 2013-05-22)
    In this study, in vitro drug testing was combined with proteomic and bioinformatic analyses to identify and characterize proteins involved in larval development of Oesophagostomum dentatum, an economically important parasitic nematode. Four hydrolase inhibitors ο-phenanthroline, sodium fluoride, iodoacetamide and 1,2-epoxy-3-(pnitrophenoxy)-propane (EPNP) significantly inhibited (≥90%) larval development. Comparison of the proteomic profiles of the development-inhibited larvae with those of uninhibited control larvae using two-dimensional gel electrophoresis, and subsequent MALDI-TOF mass spectrometric analysis identified a down-regulation of 12 proteins inferred to be involved in various larval developmental processes, including post-embryonic development and growth. Furthermore, three proteins (i.e. intermediate filament protein B, tropomyosin and peptidyl-prolyl cis-trans isomerase) inferred to be involved in the moulting process were down-regulated in moulting- and development-inhibited O. dentatum larvae. This first proteomic map of O. dentatum larvae provides insights in the protein profile of larval development in this parasitic nematode, and significantly improves our understanding of the fundamental biology of its development. The results and the approach used might assist in developing new interventions against parasitic nematodes by blocking or disrupting their key biological pathways.
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    SchistoDB: an updated genome resource for the three key schistosomes of humans
    Zerlotini, A ; Aguiar, ERGR ; Yu, F ; Xu, H ; Li, Y ; Young, ND ; Gasser, RB ; Protasio, AV ; Berriman, M ; Roos, DS ; Kissinger, JC ; Oliveira, G (OXFORD UNIV PRESS, 2013-01-01)
    The new release of SchistoDB (http://SchistoDB.net) provides a rich resource of genomic data for key blood flukes (genus Schistosoma) which cause disease in hundreds of millions of people worldwide. SchistoDB integrates whole-genome sequence and annotation of three species of the genus and provides enhanced bioinformatics analyses and data-mining tools. A simple, yet comprehensive web interface provided through the Strategies Web Development Kit is available for the mining and visualization of the data. Genomic scale data can be queried based on BLAST searches, annotation keywords and gene ID searches, gene ontology terms, sequence motifs, protein characteristics and phylogenetic relationships. Search strategies can be saved within a user's profile for future retrieval and may also be shared with other researchers using a unique web address.
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    Insights into SCP/TAPS Proteins of Liver Flukes Based on Large-Scale Bioinformatic Analyses of Sequence Datasets
    Cantacessi, C ; Hofmann, A ; Young, ND ; Broder, U ; Hall, RS ; Loukas, A ; Gasser, RB ; Seo, J-S (PUBLIC LIBRARY SCIENCE, 2012-02-22)
    BACKGROUND: SCP/TAPS proteins of parasitic helminths have been proposed to play key roles in fundamental biological processes linked to the invasion of and establishment in their mammalian host animals, such as the transition from free-living to parasitic stages and the modulation of host immune responses. Despite the evidence that SCP/TAPS proteins of parasitic nematodes are involved in host-parasite interactions, there is a paucity of information on this protein family for parasitic trematodes of socio-economic importance. METHODOLOGY/PRINCIPAL FINDINGS: We conducted the first large-scale study of SCP/TAPS proteins of a range of parasitic trematodes of both human and veterinary importance (including the liver flukes Clonorchis sinensis, Opisthorchis viverrini, Fasciola hepatica and F. gigantica as well as the blood flukes Schistosoma mansoni, S. japonicum and S. haematobium). We mined all current transcriptomic and/or genomic sequence datasets from public databases, predicted secondary structures of full-length protein sequences, undertook systematic phylogenetic analyses and investigated the differential transcription of SCP/TAPS genes in O. viverrini and F. hepatica, with an emphasis on those that are up-regulated in the developmental stages infecting the mammalian host. CONCLUSIONS: This work, which sheds new light on SCP/TAPS proteins, guides future structural and functional explorations of key SCP/TAPS molecules associated with diseases caused by flatworms. Future fundamental investigations of these molecules in parasites and the integration of structural and functional data could lead to new approaches for the control of parasitic diseases.
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    Molecular Changes in Opisthorchis viverrini (Southeast Asian Liver Fluke) during the Transition from the Juvenile to the Adult Stage
    Jex, AR ; Young, ND ; Sripa, J ; Hall, RS ; Scheerlinck, J-P ; Laha, T ; Sripa, B ; Gasser, RB ; Jones, MK (PUBLIC LIBRARY SCIENCE, 2012-11-01)
    BACKGROUND: The Southeast Asian liver fluke (Opisthorchis viverrini) chronically infects and affects tens of millions of people in regions of Asia, leading to chronic illness and, importantly, inducing malignant cancer (= cholangiocarcinoma). In spite of this, little is known, at the molecular level, about the parasite itself, its interplay with its hosts or the mechanisms of disease and/or carcinogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Here, we generated extensive RNA-Seq data (Illumina) representing adult and juvenile stages of O. viverrini, and combined these sequences with previously published transcriptomic data (454 technology) for this species, yielding a combined assembly of significantly increased quality and allowing quantitative assessment of transcription in the juvenile and adult stage. CONCLUSIONS: This enhanced assembly reveals that, despite the substantial biological similarities between the human liver flukes, O. viverinni and Clonorchis sinensis, there are previously unrecognized differences in major aspects of their molecular biology. Most notable are differences among the C13 and cathepsin L-like cysteine peptidases, which play key roles in tissue migration, immune evasion and feeding, and, thus, represent potential drug and/or vaccine targets. Furthermore, these data indicate that major lineages of cysteine peptidases of socioeconomically important trematodes have evolved through a process of gene loss rather than independent radiation, contrasting previous proposals.
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    The Transcriptome of Trichuris suis - First Molecular Insights into a Parasite with Curative Properties for Key Immune Diseases of Humans
    Cantacessi, C ; Young, ND ; Nejsum, P ; Jex, AR ; Campbell, BE ; Hall, RS ; Thamsborg, SM ; Scheerlinck, J-P ; Gasser, RB ; Hofmann, A (PUBLIC LIBRARY SCIENCE, 2011-08-24)
    BACKGROUND: Iatrogenic infection of humans with Trichuris suis (a parasitic nematode of swine) is being evaluated or promoted as a biological, curative treatment of immune diseases, such as inflammatory bowel disease (IBD) and ulcerative colitis, in humans. Although it is understood that short-term T. suis infection in people with such diseases usually induces a modified Th2-immune response, nothing is known about the molecules in the parasite that induce this response. METHODOLOGY/PRINCIPAL FINDINGS: As a first step toward filling the gaps in our knowledge of the molecular biology of T. suis, we characterised the transcriptome of the adult stage of this nematode employing next-generation sequencing and bioinformatic techniques. A total of ∼65,000,000 reads were generated and assembled into ∼20,000 contiguous sequences ( = contigs); ∼17,000 peptides were predicted and classified based on homology searches, protein motifs and gene ontology and biological pathway mapping. CONCLUSIONS: These analyses provided interesting insights into a number of molecular groups, particularly predicted excreted/secreted molecules (n = 1,288), likely to be involved in the parasite-host interactions, and also various molecules (n = 120) linked to chemokine, T-cell receptor and TGF-β signalling as well as leukocyte transendothelial migration and natural killer cell-mediated cytotoxicity, which are likely to be immuno-regulatory or -modulatory in the infected host. This information provides a conceptual framework within which to test the immunobiological basis for the curative effect of T. suis infection in humans against some immune diseases. Importantly, the T. suis transcriptome characterised herein provides a curated resource for detailed studies of the immuno-molecular biology of this parasite, and will underpin future genomic and proteomic explorations.
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    A Portrait of the Transcriptome of the Neglected Trematode, Fasciola gigantica-Biological and Biotechnological Implications
    Young, ND ; Jex, AR ; Cantacessi, C ; Hall, RS ; Campbell, BE ; Spithill, TW ; Tangkawattana, S ; Tangkawattana, P ; Laha, T ; Gasser, RB ; Ghedin, E (PUBLIC LIBRARY SCIENCE, 2011-02-01)
    Fasciola gigantica (Digenea) is an important foodborne trematode that causes liver fluke disease (fascioliasis) in mammals, including ungulates and humans, mainly in tropical climatic zones of the world. Despite its socioeconomic impact, almost nothing is known about the molecular biology of this parasite, its interplay with its hosts, and the pathogenesis of fascioliasis. Modern genomic technologies now provide unique opportunities to rapidly tackle these exciting areas. The present study reports the first transcriptome representing the adult stage of F. gigantica (of bovid origin), defined using a massively parallel sequencing-coupled bioinformatic approach. From >20 million raw sequence reads, >30,000 contiguous sequences were assembled, of which most were novel. Relative levels of transcription were determined for individual molecules, which were also characterized (at the inferred amino acid level) based on homology, gene ontology, and/or pathway mapping. Comparisons of the transcriptome of F. gigantica with those of other trematodes, including F. hepatica, revealed similarities in transcription for molecules inferred to have key roles in parasite-host interactions. Overall, the present dataset should provide a solid foundation for future fundamental genomic, proteomic, and metabolomic explorations of F. gigantica, as well as a basis for applied outcomes such as the development of novel methods of intervention against this neglected parasite.
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    Massively Parallel Sequencing and Analysis of the Necator americanus Transcriptome
    Cantacessi, C ; Mitreva, M ; Jex, AR ; Young, ND ; Campbell, BE ; Hall, RS ; Doyle, MA ; Ralph, SA ; Rabelo, EM ; Ranganathan, S ; Sternberg, PW ; Loukas, A ; Gasser, RB ; Knight, M (PUBLIC LIBRARY SCIENCE, 2010-05-01)
    BACKGROUND: The blood-feeding hookworm Necator americanus infects hundreds of millions of people worldwide. In order to elucidate fundamental molecular biological aspects of this hookworm, the transcriptome of the adult stage of Necator americanus was explored using next-generation sequencing and bioinformatic analyses. METHODOLOGY/PRINCIPAL FINDINGS: A total of 19,997 contigs were assembled from the sequence data; 6,771 of these contigs had known orthologues in the free-living nematode Caenorhabditis elegans, and most of them encoded proteins with WD40 repeats (10.6%), proteinase inhibitors (7.8%) or calcium-binding EF-hand proteins (6.7%). Bioinformatic analyses inferred that the C. elegans homologues are involved mainly in biological pathways linked to ribosome biogenesis (70%), oxidative phosphorylation (63%) and/or proteases (60%); most of these molecules were predicted to be involved in more than one biological pathway. Comparative analyses of the transcriptomes of N. americanus and the canine hookworm, Ancylostoma caninum, revealed qualitative and quantitative differences. For instance, proteinase inhibitors were inferred to be highly represented in the former species, whereas SCP/Tpx-1/Ag5/PR-1/Sc7 proteins ( = SCP/TAPS or Ancylostoma-secreted proteins) were predominant in the latter. In N. americanus, essential molecules were predicted using a combination of orthology mapping and functional data available for C. elegans. Further analyses allowed the prioritization of 18 predicted drug targets which did not have homologues in the human host. These candidate targets were inferred to be linked to mitochondrial (e.g., processing proteins) or amino acid metabolism (e.g., asparagine t-RNA synthetase). CONCLUSIONS: This study has provided detailed insights into the transcriptome of the adult stage of N. americanus and examines similarities and differences between this species and A. caninum. Future efforts should focus on comparative transcriptomic and proteomic investigations of the other predominant human hookworm, A. duodenale, for both fundamental and applied purposes, including the prevalidation of anti-hookworm drug targets.
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    Unlocking the Transcriptomes of Two Carcinogenic Parasites, Clonorchis sinensis and Opisthorchis viverrini
    Young, ND ; Campbell, BE ; Hall, RS ; Jex, AR ; Cantacessi, C ; Laha, T ; Sohn, W-M ; Sripa, B ; Loukas, A ; Brindley, PJ ; Gasser, RB ; Jones, MK (PUBLIC LIBRARY SCIENCE, 2010-06-01)
    The two parasitic trematodes, Clonorchis sinensis and Opisthorchis viverrini, have a major impact on the health of tens of millions of humans throughout Asia. The greatest impact is through the malignant cancer ( = cholangiocarcinoma) that these parasites induce in chronically infected people. Therefore, both C. sinensis and O. viverrini have been classified by the World Health Organization (WHO) as Group 1 carcinogens. Despite their impact, little is known about these parasites and their interplay with the host at the molecular level. Recent advances in genomics and bioinformatics provide unique opportunities to gain improved insights into the biology of parasites as well as their relationships with their hosts at the molecular level. The present study elucidates the transcriptomes of C. sinensis and O. viverrini using a platform based on next-generation (high throughput) sequencing and advanced in silico analyses. From 500,000 sequences, >50,000 sequences were assembled for each species and categorized as biologically relevant based on homology searches, gene ontology and/or pathway mapping. The results of the present study could assist in defining molecules that are essential for the development, reproduction and survival of liver flukes and/or that are linked to the development of cholangiocarcinoma. This study also lays a foundation for future genomic and proteomic research of C. sinensis and O. viverrini and the cancers that they are known to induce, as well as novel intervention strategies.