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)
    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)
    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)
    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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    The Opisthorchis viverrini genome provides insights into life in the bile duct
    Young, ND ; Nagarajan, N ; Lin, SJ ; Korhonen, PK ; Jex, AR ; Hall, RS ; Safavi-Hemami, H ; Kaewkong, W ; Bertrand, D ; Gao, S ; Seet, Q ; Wongkham, S ; Teh, BT ; Wongkham, C ; Intapan, PM ; Maleewong, W ; Yang, X ; Hu, M ; Wang, Z ; Hofmann, A ; Sternberg, PW ; Tan, P ; Wang, J ; Gasser, RB (NATURE PUBLISHING GROUP, 2014-07)
    Opisthorchiasis is a neglected, tropical disease caused by the carcinogenic Asian liver fluke, Opisthorchis viverrini. This hepatobiliary disease is linked to malignant cancer (cholangiocarcinoma, CCA) and affects millions of people in Asia. No vaccine is available, and only one drug (praziquantel) is used against the parasite. Little is known about O. viverrini biology and the diseases that it causes. Here we characterize the draft genome (634.5 Mb) and transcriptomes of O. viverrini, elucidate how this fluke survives in the hostile environment within the bile duct and show that metabolic pathways in the parasite are highly adapted to a lipid-rich diet from bile and/or cholangiocytes. We also provide additional evidence that O. viverrini and other flukes secrete proteins that directly modulate host cell proliferation. Our molecular resources now underpin profound explorations of opisthorchiasis/CCA and the design of new interventions.
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    Transcriptional analysis identifies key genes involved in metabolism, fibrosis/tissue repair and the immune response against Fasciola hepatica in sheep liver
    Alvarez Rojas, CA ; Ansell, BRE ; Hall, RS ; Gasser, RB ; Young, ND ; Jex, AR ; Scheerlinck, J-PY (BMC, 2015-02-25)
    BACKGROUND: Although fascioliasis has been relatively well studied, little is known about the molecular basis of this disease. This is particularly relevant, considering the very different response that sheep have to Fasciola hepatica relative to cattle. The acute phase of this disease is severe in sheep, whereas chronic fascioliasis is more common in cattle. METHODS: To begin to explore the host-response to Fasciola in sheep and improve the understanding of the host-pathogen interactions during the parasite's migration through liver parenchyma to the bile duct, we used RNA sequencing (RNA-seq) to investigate livers from sheep infected for eight weeks compared with those from uninfected controls. RESULTS: This study identified 572 and 42 genes that were up- and down-regulated, respectively, in infected livers relative to uninfected controls. Our molecular findings provide significant new insights into the mechanisms linked to metabolism, fibrosis and tissue-repair in sheep, and highlight the relative importance of specific components of immune response pathways, which appear to be driven toward a suppression of inflammation. CONCLUSIONS: This study is, to our knowledge, the first detailed investigation of the transcriptomic responses in the liver tissue of any host to F. hepatica infection. It defines the involvement of specific genes associated with the host's metabolism, immune response and tissue repair/regeneration, and highlights an apparent overlapping function of many genes involved in these processes.
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    Complete mitochondrial genomes of the 'intermediate form' of Fasciola and Fasciola gigantica, and their comparison with F. hepatica
    Liu, G-H ; Gasser, RB ; Young, ND ; Song, H-Q ; Ai, L ; Zhu, X-Q (BIOMED CENTRAL LTD, 2014-03-31)
    BACKGROUND: Fascioliasis is an important and neglected disease of humans and other mammals, caused by trematodes of the genus Fasciola. Fasciola hepatica and F. gigantica are valid species that infect humans and animals, but the specific status of Fasciola sp. ('intermediate form') is unclear. METHODS: Single specimens inferred to represent Fasciola sp. ('intermediate form'; Heilongjiang) and F. gigantica (Guangxi) from China were genetically identified and characterized using PCR-based sequencing of the first and second internal transcribed spacer regions of nuclear ribosomal DNA. The complete mitochondrial (mt) genomes of these representative specimens were then sequenced. The relationships of these specimens with selected members of the Trematoda were assessed by phylogenetic analysis of concatenated amino acid sequence datasets by Bayesian inference (BI). RESULTS: The complete mt genomes of representatives of Fasciola sp. and F. gigantica were 14,453 bp and 14,478 bp in size, respectively. Both mt genomes contain 12 protein-coding genes, 22 transfer RNA genes and two ribosomal RNA genes, but lack an atp8 gene. All protein-coding genes are transcribed in the same direction, and the gene order in both mt genomes is the same as that published for F. hepatica. Phylogenetic analysis of the concatenated amino acid sequence data for all 12 protein-coding genes showed that the specimen of Fasciola sp. was more closely related to F. gigantica than to F. hepatica. CONCLUSIONS: The mt genomes characterized here provide a rich source of markers, which can be used in combination with nuclear markers and imaging techniques, for future comparative studies of the biology of Fasciola sp. from China and other countries.
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    Genetic blueprint of the zoonotic pathogen Toxocara canis
    Zhu, X-Q ; Korhonen, PK ; Cai, H ; Young, ND ; Nejsum, P ; von Samson-Himmelstjerna, G ; Boag, PR ; Tan, P ; Li, Q ; Min, J ; Yang, Y ; Wang, X ; Fang, X ; Hall, RS ; Hofmann, A ; Sternberg, PW ; Jex, AR ; Gasser, RB (NATURE RESEARCH, 2015-02)
    Toxocara canis is a zoonotic parasite of major socioeconomic importance worldwide. In humans, this nematode causes disease (toxocariasis) mainly in the under-privileged communities in developed and developing countries. Although relatively well studied from clinical and epidemiological perspectives, to date, there has been no global investigation of the molecular biology of this parasite. Here we use next-generation sequencing to produce a draft genome and transcriptome of T. canis to support future biological and biotechnological investigations. This genome is 317 Mb in size, has a repeat content of 13.5% and encodes at least 18,596 protein-coding genes. We study transcription in a larval, as well as adult female and male stages, characterize the parasite's gene-silencing machinery, explore molecules involved in development or host-parasite interactions and predict intervention targets. The draft genome of T. canis should provide a useful resource for future molecular studies of this and other, related parasites.
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    Exploring molecular variation in Schistosoma japonicum in China
    Young, ND ; Chan, K-G ; Korhonen, PK ; Chong, TM ; Ee, R ; Mohandas, N ; Koehler, AV ; Lim, Y-L ; Hofmann, A ; Jex, AR ; Qian, B ; Chilton, NB ; Gobert, GN ; McManus, DP ; Tan, P ; Webster, BL ; Rollinson, D ; Gasser, RB (NATURE PORTFOLIO, 2015-12-01)
    Schistosomiasis is a neglected tropical disease that affects more than 200 million people worldwide. The main disease-causing agents, Schistosoma japonicum, S. mansoni and S. haematobium, are blood flukes that have complex life cycles involving a snail intermediate host. In Asia, S. japonicum causes hepatointestinal disease (schistosomiasis japonica) and is challenging to control due to a broad distribution of its snail hosts and range of animal reservoir hosts. In China, extensive efforts have been underway to control this parasite, but genetic variability in S. japonicum populations could represent an obstacle to eliminating schistosomiasis japonica. Although a draft genome sequence is available for S. japonicum, there has been no previous study of molecular variation in this parasite on a genome-wide scale. In this study, we conducted the first deep genomic exploration of seven S. japonicum populations from mainland China, constructed phylogenies using mitochondrial and nuclear genomic data sets, and established considerable variation between some of the populations in genes inferred to be linked to key cellular processes and/or pathogen-host interactions. Based on the findings from this study, we propose that verifying intraspecific conservation in vaccine or drug target candidates is an important first step toward developing effective vaccines and chemotherapies against schistosomiasis.
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    The Haemonchus contortus kinome - a resource for fundamental molecular investigations and drug discovery
    Stroehlein, AJ ; Young, ND ; Korhonen, PK ; Jabbar, A ; Hofmann, A ; Sternberg, PW ; Gasser, RB (BMC, 2015-12-08)
    BACKGROUND: Protein kinases regulate a plethora of essential signalling and other biological pathways in all eukaryotic organisms, but very little is known about them in most parasitic nematodes. METHODS: Here, we defined, for the first time, the entire complement of protein kinases (kinome) encoded in the barber's pole worm (Haemonchus contortus) through an integrated analysis of transcriptomic and genomic datasets using an advanced bioinformatic workflow. RESULTS: We identified, curated and classified 432 kinases representing ten groups, 103 distinct families and 98 subfamilies. A comparison of the kinomes of H. contortus and Caenorhabditis elegans (a related, free-living nematode) revealed considerable variation in the numbers of casein kinases, tyrosine kinases and Ca(2+)/calmodulin-dependent protein kinases, which likely relate to differences in biology, habitat and life cycle between these worms. Moreover, a suite of kinase genes was selectively transcribed in particular developmental stages of H. contortus, indicating central roles in developmental and reproductive processes. In addition, using a ranking system, drug targets (n = 13) and associated small-molecule effectors (n = 1517) were inferred. CONCLUSIONS: The H. contortus kinome will provide a useful resource for fundamental investigations of kinases and signalling pathways in this nematode, and should assist future anthelmintic discovery efforts; this is particularly important, given current drug resistance problems in parasitic nematodes.