Veterinary Biosciences - Research Publications

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    Global prevalence of Ascaris infection in humans (2010-2021): a systematic review and meta-analysis.
    Holland, C ; Sepidarkish, M ; Deslyper, G ; Abdollahi, A ; Valizadeh, S ; Mollalo, A ; Mahjour, S ; Ghodsian, S ; Ardekani, A ; Behniafar, H ; Gasser, RB ; Rostami, A (Springer Science and Business Media LLC, 2022-11-18)
    BACKGROUND: Ascariasis is one of the most important neglected tropical diseases of humans worldwide. The epidemiology of Ascaris infection appears to have changed with improvements in sanitation and mass drug administration, but there is no recent information on prevalence worldwide. Here, we performed a systematic review and meta-analysis to assess the global prevalence of human Ascaris infection from 2010 to 2021. METHODS: We searched MEDLINE/PubMed, and Scopus databases for studies measuring prevalence of Ascaris infection, published between 1 January 2010 and 1 January 2022. We included studies of the general human population in endemic regions, which used accepted coprodiagnostic methods, and excluded studies of people with occupations with an increased risk or probability of ascariasis and/or specific diseases other than ascariasis. We applied random-effects models to obtain pooled prevalence estimates for six sustainable development goal regions of the world. We extrapolated the prevalence estimates to the global population in 2020, to estimate the number of individuals with Ascaris infection. We conducted multiple subgroup and meta-regression analyses to explore possible sources of heterogeneity, and to assess relationships between prevalence estimates and demographic, socio-economic, geo-climatic factors. RESULTS: Of 11,245 studies screened, we analysed 758 prevalence estimates for a total number of 4,923,876 participants in 616 studies from 81 countries. The global prevalence estimated was 11.01% (95% confidence interval: 10.27-11.78%), with regional prevalences ranging from 28.77% (7.07-57.66%) in Melanesia (Oceania) to 1.39% (1.07-1.74%) in Eastern Asia. We estimated that ~ 732 (682-782) million people harboured Ascaris worldwide in 2021. The infected people in Latin America and the Caribbean region had a higher prevalence of high intensity infection (8.4%, 3.9-14.1%). Prevalence estimates were higher in children, and people in rural communities or in countries or regions with lower income and human development indices. There was a trend for a higher prevalence in regions with increasing mean annual relative humidity, precipitation and environmental temperature. CONCLUSIONS: Our findings indicate that, despite a renewed commitment by some communities or authorities to control ascariasis, a substantial portion of the world's human population (> 0.7 billion) is infected with Ascaris. Despite the clinical and socioeconomic importance of ascariasis, many past routine surveys did not assess the intensity of Ascaris infection in people. We propose that the present findings might stimulate the development of customised strategies for the improved control and prevention of Ascaris infection worldwide.
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    H11-induced immunoprotection is predominantly linked to N-glycan moieties during Haemonchus contortus infection.
    Wang, C ; Liu, L ; Wang, T ; Liu, X ; Peng, W ; Srivastav, RK ; Zhu, X-Q ; Gupta, N ; Gasser, RB ; Hu, M (Frontiers Media SA, 2022)
    Nematodes are one of the largest groups of animals on the planet. Many of them are major pathogens of humans, animals and plants, and cause destructive diseases and socioeconomic losses worldwide. Despite their adverse impacts on human health and agriculture, nematodes can be challenging to control, because anthelmintic treatments do not prevent re-infection, and excessive treatment has led to widespread drug resistance in nematode populations. Indeed, many nematode species of livestock animals have become resistant to almost all classes of anthelmintics used. Most efforts to develop commercial anti-nematode vaccines (native or recombinant) for use in animals and humans have not succeeded, although one effective (dead) vaccine (Barbervax) has been developed to protect animals against one of the most pathogenic parasites of livestock animals - Haemonchus contortus (the barber's pole worm). This vaccine contains native molecules, called H11 and H-Gal-GP, derived from the intestine of this blood-feeding worm. In its native form, H11 alone consistently induces high levels (75-95%) of immunoprotection in animals against disease (haemonchosis), but recombinant forms thereof do not. Here, to test the hypothesis that post-translational modification (glycosylation) of H11 plays a crucial role in achieving such high immunoprotection, we explored the N-glycoproteome and N-glycome of H11 using the high-resolution mass spectrometry and assessed the roles of N-glycosylation in protective immunity against H. contortus. Our results showed conclusively that N-glycan moieties on H11 are the dominant immunogens, which induce high IgG serum antibody levels in immunised animals, and that anti-H11 IgG antibodies can confer specific, passive immunity in naïve animals. This work provides the first detailed account of the relevance and role of protein glycosylation in protective immunity against a parasitic nematode, with important implications for the design of vaccines against metazoan parasites.
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    Proteomic analysis of Sarcoptes scabiei reveals that proteins differentially expressed between eggs and female adult stages are involved predominantly in genetic information processing, metabolism and/or host-parasite interactions
    Wang, T ; Gasser, RB ; Korhonen, PK ; Young, ND ; Ang, C-S ; Williamson, NA ; Ma, G ; Samarawickrama, GR ; Fernando, DD ; Fischer, K ; Taylan Ozkan, A (PUBLIC LIBRARY SCIENCE, 2022-12)
    Presently, there is a dearth of proteomic data for parasitic mites and their relationship with the host animals. Here, using a high throughput LC-MS/MS-based approach, we undertook the first comprehensive, large-scale proteomic investigation of egg and adult female stages of the scabies mite, Sarcoptes scabiei-one of the most important parasitic mites of humans and other animals worldwide. In total, 1,761 S. scabiei proteins were identified and quantified with high confidence. Bioinformatic analyses revealed differentially expressed proteins to be involved predominantly in biological pathways or processes including genetic information processing, energy (oxidative phosphorylation), nucleotide, amino acid, carbohydrate and/or lipid metabolism, and some adaptive processes. Selected, constitutively and highly expressed proteins, such as peptidases, scabies mite inactivated protease paralogues (SMIPPs) and muscle proteins (myosin and troponin), are proposed to be involved in key biological processes within S. scabiei, host-parasite interactions and/or the pathogenesis of scabies. These proteomic data will enable future molecular, biochemical and physiological investigations of early developmental stages of S. scabiei and the discovery of novel interventions, targeting the egg stage, given its non-susceptibility to acaricides currently approved for the treatment of scabies in humans.
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    Identification of Anthelmintic Bishomoscalarane Sesterterpenes from the Australian Marine Sponge Phyllospongia bergquistae and Structure Revision of Phyllolactones A-D
    Hayes, S ; Taki, AC ; Lum, KY ; Byrne, JJ ; White, JM ; Ekins, MG ; Gasser, RB ; Davis, RA (AMER CHEMICAL SOC, 2022-07-22)
    High-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract derived from the Australian marine sponge Phyllospongia bergquistae with activity against Hemonchus contortus (barber's pole worm), an economically important parasitic nematode. Bioassay-guided fractionation of the CH2Cl2/MeOH extract from P. bergquistae led to the purification of four known bishomoscalarane sesterterpenes, phyllolactones A-D (1-4). The absolute configurations of phyllolactones B (2) and C (3) were determined by single-crystal X-ray diffraction analysis; literature and data analyses revealed the need for these chemical structures to be revised. Compounds 2-4 induced a lethal, skinny (Ski) phenotype in larvae of H. contortus at concentrations between 5.3 and 10.1 μM. These data indicate that the bishomoscalarane sesterterpene structure class warrants further investigation for nematocidal or nematostatic activity.
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    Ubiquitination pathway model for the barber's pole worm - Haemonchus contortus
    Zheng, Y ; Ma, G ; Wang, T ; Hofmann, A ; Song, J ; Gasser, RB ; Young, ND (ELSEVIER SCI LTD, 2022-08)
    The ubiquitin-mediated pathway has been comprehensively explored in the free-living nematode Caenorhabditis elegans, but very little is known about this pathway in parasitic nematodes. Here, we inferred the ubiquitination pathway for an economically significant and pathogenic nematode - Haemonchus contortus - using abundant resources available for C. elegans. We identified 215 genes encoding ubiquitin (Ub; n = 3 genes), ubiquitin-activating enzyme (E1; one), -conjugating enzymes (E2s; 21), ligases (E3s; 157) and deubiquitinating enzymes (DUBs; 33). With reference to C. elegans, Ub, E1 and E2 were relatively conserved in sequence and structure, and E3s and DUBs were divergent, likely reflecting functional and biological uniqueness in H. contortus. Most genes encoding ubiquitination pathway components exhibit high transcription in the egg compared with other stages, indicating marked protein homeostasis in this early developmental stage. The ubiquitination pathway model constructed for H. contortus provides a foundation to explore the ubiquitin-proteasome system, crosstalk between autophagy and the proteasome system, and the parasite-host interactions. Selected E3 and DUB proteins which are very divergent in sequence and structure from host homologues or entirely unique to H. contortus and related parasitic nematodes may represent possible anthelmintic targets.
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    Using UHPLC-MS profiling for the discovery of new sponge-derived metabolites and anthelmintic screening of the NatureBank bromotyrosine library
    Hayes, S ; Taki, AC ; Lum, KY ; Byrne, JJ ; Ekins, MG ; Gasser, RB ; Davis, RA (BEILSTEIN-INSTITUT, 2022-11-15)
    In order to further expand the NatureBank open access compound library, chemical investigations of the Australian marine sponge, Ianthella basta, were undertaken since UHPLC-MS analysis of the extract from this sponge indicated the presence of a new alkaloid. Large-scale extraction and mass-directed isolation studies on the CH2Cl2/MeOH I. basta extract resulted in the purification of a new bromotyrosine-derived alkaloid, 5-debromopurealidin H (1), along with the known marine natural product, ianthesine E (2). The chemical structure of the new compound was determined following detailed spectroscopic and spectrometric data analysis. These two compounds (1 and 2) along with seven previously reported marine bromotyrosine alkaloids from the NatureBank open access library, which included psammaplysins F (3) and H (4), bastadins 4 (5), 8 (6) and 13 (7), aerothionin (8) and hexadellin A (9), were evaluated for their nematocidal activity against exsheathed third-stage larvae of Haemonchus contortus, a highly pathogenic parasite of ruminants. Of the nine compounds, bastadin 8 (6), hexadellin A (9) and bastadin 4 (5) showed inhibition towards larval motility after 72 h of exposure with IC50 values of 1.6 µM, 10.0 µM and 33.3 µM, respectively.
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    The non-glycosylated protein of Toxocara canis MUC-1 interacts with proteins of murine macrophages
    Zhou, R ; Jia, H ; Du, Z ; Jiang, A ; Song, Z ; Wang, T ; Du, A ; Gasser, RBB ; Ma, G ; Cwiklinski, K (PUBLIC LIBRARY SCIENCE, 2022-09)
    Toxocariasis is a neglected parasitic disease caused predominantly by larvae of Toxocara canis. While this zoonotic disease is of major importance in humans and canids, it can also affect a range of other mammalian hosts. It is known that mucins secreted by larvae play key roles in immune recognition and evasion, but very little is understood about the molecular interactions between host cells and T. canis. Here, using an integrative approach (affinity pull-down, mass spectrometry, co-immunoprecipitation and bioinformatics), we identified 219 proteins expressed by a murine macrophage cell line (RAW264.7) that interact with prokaryotically-expressed recombinant protein (rTc-MUC-1) representing the mucin Tc-MUC-1 present in the surface coat of infective larvae of T. canis. Protein-protein interactions between rTc-MUC-1 and an actin binding protein CFL1 as well as the fatty acid binding protein FABP5 of RAW264.7 macrophages were also demonstrated in a human embryonic kidney cell line (HEK 293T). By combing predicted structural information on the protein-protein interaction and functional knowledge of the related protein association networks, we inferred roles for Tc-MUC-1 protein in the regulation of actin cytoskeletal remodelling, and the migration and phagosome formation of macrophage cells. These molecular interactions now require verification in vivo. The experimental approach taken here should be readily applicable to comparative studies of other ascaridoid nematodes (e.g. T. cati, Anisakis simplex, Ascaris suum and Baylisascaris procyonis) whose larvae undergo tissue migration in accidental hosts, including humans.
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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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    Novel High-Throughput Fluorescence-Based Assay for the Identification of Nematocidal Compounds That Target the Blood-Feeding Pathway
    Marchand, A ; Van Bree, JWM ; Taki, AC ; Moyat, M ; Turcatti, G ; Chambon, M ; Smith, AAT ; Doolan, R ; Gasser, RB ; Harris, NL ; Bouchery, T (MDPI, 2022-06)
    Hookworm infections cause a neglected tropical disease (NTD) affecting ~740 million people worldwide, principally those living in disadvantaged communities. Infections can cause high morbidity due to their impact on nutrient uptake and their need to feed on host blood, resulting in a loss of iron and protein, which can lead to severe anaemia and impaired cognitive development in children. Currently, only one drug, albendazole is efficient to treat hookworm infection and the scientific community fears the rise of resistant strains. As part of on-going efforts to control hookworm infections and its associated morbidities, new drugs are urgently needed. We focused on targeting the blood-feeding pathway, which is essential to the parasite survival and reproduction, using the laboratory hookworm model Nippostrongylus brasiliensis (a nematode of rodents with a similar life cycle to hookworms). We established an in vitro-drug screening assay based on a fluorescent-based measurement of parasite viability during blood-feeding to identify novel therapeutic targets. A first screen of a library of 2654 natural compounds identified four that caused decreased worm viability in a blood-feeding-dependent manner. This new screening assay has significant potential to accelerate the discovery of new drugs against hookworms.