Veterinary Biosciences - Research Publications

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    Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
    Taki, ACC ; Wang, T ; Nguyen, NNN ; Ang, C-S ; Leeming, MGG ; Nie, S ; Byrne, JJJ ; Young, NDD ; Zheng, Y ; Ma, G ; Korhonen, PKK ; Koehler, AVV ; Williamson, NAA ; Hofmann, A ; Chang, BCH ; Haeberli, C ; Keiser, J ; Jabbar, A ; Sleebs, BEE ; Gasser, RBB (FRONTIERS MEDIA SA, 2022-10-14)
    Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines against parasitic nematodes have been largely unsuccessful, there is an increased focus on discovering new anthelmintic entities to combat drug resistant worms. Here, we employed thermal proteome profiling (TPP) to explore hit pharmacology and to support optimisation of a hit compound (UMW-868), identified in a high-throughput whole-worm, phenotypic screen. Using advanced structural prediction and docking tools, we inferred an entirely novel, parasite-specific target (HCO_011565) of this anthelmintic small molecule in the highly pathogenic, blood-feeding barber's pole worm, and in other socioeconomically important parasitic nematodes. The "hit-to-target" workflow constructed here provides a unique prospect of accelerating the simultaneous discovery of novel anthelmintics and associated parasite-specific targets.
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    Phylogenetic Relationships of the Strongyloid Nematodes of Australasian Marsupials Based on Mitochondrial Protein Sequences
    Sukee, T ; Beveridge, I ; Koehler, AV ; Hall, RS ; Gasser, RB ; Jabbar, A (MDPI, 2022-11)
    Australasian marsupials harbour a diverse group of gastrointestinal strongyloid nematodes. These nematodes are currently grouped into two subfamilies, namely the Cloacininae and Phascolostrongylinae. Based on morphological criteria, the Cloacininae and Phascolostrongylinae were defined as monophyletic and placed in the family Cloacinidae, but this has not been supported by molecular data and they are currently placed in the Chabertiidae. Although molecular data (internal transcribed spacers of the nuclear ribosomal RNA genes or mitochondrial protein-coding genes) have been used to verify morphological classifications within the Cloacininae and Phascolostrongylinae, the phylogenetic relationships between the subfamilies have not been rigorously tested. This study determined the phylogenetic relationships of the subfamilies Cloacininae and Phascolostrongylinae using amino acid sequences conceptually translated from the twelve concatenated mitochondrial protein-coding genes. The findings demonstrated that the Cloacininae and Phascolostrongylinae formed a well-supported monophyletic assemblage, consistent with their morphological classification as an independent family, Cloacinidae. Unexpectedly, however, the subfamily Phascolostrongylinae was split into two groups comprising the genera from macropodid hosts (kangaroos and wallabies) and those from vombatid hosts (wombats). Genera of the Cloacininae and Phascolostrongylinae occurring in macropodid hosts were more closely related compared to genera of the Phascolostrongylinae occurring in wombats that formed a sister relationship with the remaining genera from macropods. These findings provide molecular evidence supporting the monophyly of the family Cloacinidae and an alternative hypothesis for the origin of marsupial strongyloid nematodes in vombatid hosts that requires further exploration using molecular approaches and additional samples.
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    Speciation in the genus Cloacina (Nematoda: Strongylida): species flocks and intra-host speciation
    Chilton, NB ; Shuttleworth, MA ; Huby-Chilton, F ; Koehler, AV ; Jabbar, A ; Gasser, RB ; Beveridge, I (CAMBRIDGE UNIV PRESS, 2017-11)
    Sequences of the first and second internal transcribed spacers (ITS1 + ITS2) of nuclear ribosomal DNA were employed to determine whether the congeneric assemblages of species of the strongyloid nematode genus Cloacina, found in the forestomachs of individual species of kangaroos and wallabies (Marsupialia: Macropodidae), considered to represent species flocks, were monophyletic. Nematode assemblages examined in the black-striped wallaby, Macropus (Notamacropus) dorsalis, the wallaroos, Macropus (Osphranter) antilopinus/robustus, rock wallabies, Petrogale spp., the quokka, Setonix brachyurus, and the swamp wallaby, Wallabia bicolor, were not monophyletic and appeared to have arisen by host colonization. However, a number of instances of within-host speciation were detected, suggesting that a variety of methods of speciation have contributed to the evolution of the complex assemblages of species present in this genus.
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    Screening of a small, well-curated natural product-based library identifies two rotenoids with potent nematocidal activity against Haemonchus contortus
    Herath, HMPD ; Preston, S ; Hofmann, A ; Davis, RA ; Koehler, AV ; Chang, BCH ; Jabbar, A ; Gasser, RB (ELSEVIER SCIENCE BV, 2017-09-15)
    The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n=400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to some vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes, and to assess its potential as an anthelmintic candidate.
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    Chromosome-scale Echinococcus granulosus (genotype G1) genome reveals the Eg95 gene family and conservation of the EG95-vaccine molecule
    Korhonen, PK ; Kinkar, L ; Young, ND ; Cai, H ; Lightowlers, MW ; Gauci, C ; Jabbar, A ; Chang, BCH ; Wang, T ; Hofmann, A ; Koehler, A ; Li, J ; Li, J ; Wang, D ; Yin, J ; Yang, H ; Jenkins, DJ ; Saarma, U ; Laurimae, T ; Rostami-Nejad, M ; Irshadullah, M ; Mirhendi, H ; Sharbatkhori, M ; Ponce-Gordo, F ; Simsek, S ; Casulli, A ; Zait, H ; Atoyan, H ; de la Rue, ML ; Romig, T ; Wassermann, M ; Aghayan, SA ; Gevorgyan, H ; Yang, B ; Gasser, RB (NATURE PORTFOLIO, 2022-03-03)
    Cystic echinococcosis is a socioeconomically important parasitic disease caused by the larval stage of the canid tapeworm Echinococcus granulosus, afflicting millions of humans and animals worldwide. The development of a vaccine (called EG95) has been the most notable translational advance in the fight against this disease in animals. However, almost nothing is known about the genomic organisation/location of the family of genes encoding EG95 and related molecules, the extent of their conservation or their functions. The lack of a complete reference genome for E. granulosus genotype G1 has been a major obstacle to addressing these areas. Here, we assembled a chromosomal-scale genome for this genotype by scaffolding to a high quality genome for the congener E. multilocularis, localised Eg95 gene family members in this genome, and evaluated the conservation of the EG95 vaccine molecule. These results have marked implications for future explorations of aspects such as developmentally-regulated gene transcription/expression (using replicate samples) for all E. granulosus stages; structural and functional roles of non-coding genome regions; molecular 'cross-talk' between oncosphere and the immune system; and defining the precise function(s) of EG95. Applied aspects should include developing improved tools for the diagnosis and chemotherapy of cystic echinococcosis of humans.
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    Phylogenetic relationships of the nematode subfamily Phascolostrongylinae from macropodid and vombatid marsupials inferred using mitochondrial protein sequence data
    Sukee, T ; Beveridge, I ; Koehler, A ; Hall, R ; Gasser, RB ; Jabbar, A (BMC, 2021-10-09)
    BACKGROUND: The subfamily Phascolostrongylinae (Superfamily Strongyloidea) comprises nematodes that are parasitic in the gastrointestinal tracts of macropodid (Family Macropodidae) and vombatid (Family Vombatidae) marsupials. Currently, nine genera and 20 species have been attributed to the subfamily Phascolostrongylinae. Previous studies using sequence data sets for the internal transcribed spacers (ITS) of nuclear ribosomal DNA showed conflicting topologies between the Phascolostrongylinae and related subfamilies. Therefore, the aim of this study was to validate the phylogenetic relationships within the Phascolostrongylinae and its relationship with the families Chabertiidae and Strongylidae using mitochondrial amino acid sequences. METHODS: The sequences of all 12 mitochondrial protein-coding genes were obtained by next-generation sequencing of individual adult nematodes (n = 8) representing members of the Phascolostrongylinae. These sequences were conceptually translated and the phylogenetic relationships within the Phascolostrongylinae and its relationship with the families Chabertiidae and Strongylidae were inferred from aligned, concatenated amino acid sequence data sets. RESULTS: Within the Phascolostrongylinae, the wombat-specific genera grouped separately from the genera occurring in macropods. Two of the phascolostrongyline tribes were monophyletic, including Phascolostrongylinea and Hypodontinea, whereas the tribe Macropostrongyloidinea was paraphyletic. The tribe Phascolostrongylinea occurring in wombats was closely related to Oesophagostomum spp., also from the family Chabertiidae, which formed a sister relationship with the Phascolostrongylinae. CONCLUSION: The current phylogenetic relationship within the subfamily Phascolostrongylinae supports findings from a previous study based on ITS sequence data. This study contributes also to the understanding of the phylogenetic position of the subfamily Phascolostrongylinae within the Chabertiidae. Future studies investigating the relationships between the Phascolostrongylinae and Cloacininae from macropodid marsupials may advance our knowledge of the phylogeny of strongyloid nematodes in marsupials.
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    Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro.
    Dilrukshi Herath, HMP ; Song, H ; Preston, S ; Jabbar, A ; Wang, T ; McGee, SL ; Hofmann, A ; Garcia-Bustos, J ; Chang, BCH ; Koehler, AV ; Liu, Y ; Ma, Q ; Zhang, P ; Zhao, Q ; Wang, Q ; Gasser, RB (Elsevier BV, 2018-12)
    Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads.
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    Age of first infection across a range of parasite taxa in a wild mammalian population
    Combrink, L ; Glidden, CK ; Beechler, BR ; Charleston, B ; Koehler, A ; Sisson, D ; Gasser, RB ; Jabbar, A ; Jolles, AE (ROYAL SOC, 2020-02-26)
    Newborn mammals have an immature immune system that cannot sufficiently protect them against infectious diseases. However, variation in the effectiveness of maternal immunity against different parasites may couple with temporal trends in parasite exposure to influence disparities in the timing of infection risk. Determining the relationship between age and infection risk is critical in identifying the portion of a host population that contributes to parasite dynamics, as well as the parasites that regulate host recruitment. However, there are no data directly identifying timing of first infection among parasites in wildlife. Here, we took advantage of a longitudinal dataset, tracking infection status by viruses, bacteria, protists and gastro-intestinal worms in a herd of African buffalo (Syncerus caffer) to ask: how does age of first infection differ among parasite taxa? We found distinct differences in the age of first infection among parasites that aligned with the mode of transmission and parasite taxonomy. Specifically, we found that tick-borne and environmentally transmitted protists were acquired earlier than directly transmitted bacteria and viruses. These results emphasize the importance of understanding infection risk in juveniles, especially in host species where juveniles are purported to sustain parasite persistence and/or where mortality rates of juveniles influence population dynamics.
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    Targeted Next-Generation Sequencing and Informatics as an Effective Tool to Establish the Composition of Bovine Piroplasm Populations in Endemic Regions.
    Ghafar, A ; Koehler, AV ; Hall, RS ; Gauci, CG ; Gasser, RB ; Jabbar, A (MDPI AG, 2021)
    Protists of the genera Babesia and Theileria (piroplasms) cause some of the most prevalent and debilitating diseases for bovines worldwide. In this study, we established and used a next-generation sequencing-informatic approach to explore the composition of Babesia and Theileria populations in cattle and water buffalo in a country (Pakistan) endemic for these pathogens. We collected individual blood samples from cattle (n = 212) and water buffalo (n = 154), extracted genomic DNAs, PCR-amplified the V4 hypervariable region of 18S small subunit rRNA gene from piroplasms, sequenced amplicons using Illumina technology, and then analysed data using bioinformatic platforms. The results revealed piroplasms in 68.9% (252/366) samples, with overall occurrence being markedly higher in cattle (85.8%) than in water buffaloes (45.5%). Babesia (B.) occultans and Theileria (T.) lestoquardi-like species were recorded for the first time in Pakistan, and, overall, T. annulata was most commonly detected (65.8%) followed by B. bovis (7.1%), B. bigemina (4.4%), and T. orientalis (0.5%), with the genetic variability within B. bovis being pronounced. The occurrence and composition of piroplasm species varied markedly across different agro-ecological zones. The high detection of T. annulata in asymptomatic animals suggested a relatively high level of endemic stability of tropical theileriosis in the bovine population.
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    Phylogenetic Analysis of Mitogenomic Data Sets Resolves the Relationship of Seven Macropostrongyloides Species from Australian Macropodid and Vombatid Marsupials
    Sukee, T ; Koehler, A ; Hall, R ; Beveridge, I ; Gasser, RB ; Jabbar, A (MDPI, 2020-12)
    Nematodes of the genus Macropostrongyloides inhabit the large intestines or stomachs of macropodid (kangaroos and wallabies) and vombatid (wombats) marsupials. This study established the relationships of seven species of Macropostrongyloides using mitochondrial (mt) protein amino acid sequence data sets. Phylogenetic analyses revealed that species of Macropostrongyloides (M. lasiorhini, M. baylisi, M. yamagutii, M. spearei, M. mawsonae and M. woodi) from the large intestines of their hosts formed a monophyletic assemblage with strong nodal support to the exclusion of M. dissimilis from the stomach of the swamp wallaby. Furthermore, the mitochondrial protein-coding genes provided greater insights into the diversity and phylogeny of the genus Macropostrongyloides; such data sets could potentially be used to elucidate the relationships among other parasitic nematodes of Australian marsupials.