Veterinary Biosciences - Research Publications
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ItemThermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868(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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ItemPhylogenetic Relationships of the Strongyloid Nematodes of Australasian Marsupials Based on Mitochondrial Protein Sequences(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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ItemPhysiological, Biochemical, and Yield Responses of Linseed (Linum usitatissimum L.) in α-Tocopherol-Mediated Alleviation of Salinity Stress.(Frontiers Media SA, 2022)Exogenous application of antioxidants can be helpful for plants to resist salinity, which can be a potentially simple, economical, and culturally feasible approach, compared with introgression and genetic engineering. Foliar spraying of alpha-tocopherol (α-tocopherol) is an approach to improve plant growth under salinity stress. Alpha-tocopherol acts as an antioxidant preventing salinity-induced cellular oxidation. This study was designed to investigate the negative effects of salinity (0 and 120mM NaCl) on linseed (Linum usitatissimum L.) and their alleviation by foliar spraying of α-tocopherol (0, 100, and 200mg L-1). Seeds of varieties "Chandni and Roshni" were grown in sand-filled plastic pots, laid in a completely randomized design in a factorial arrangement, and each treatment was replicated three times. Salinity significantly affected linseed morphology and yield by reducing shoot and root dry weights, photosynthetic pigment (Chl. a, Chl. b, total Chl., and carotenoids) contents, mineral ion (Ca2+, K+) uptake, and 100-seed weight. Concomitantly, salinity increased Na+, proline, soluble protein, peroxidase, catalase, and superoxide dismutase activities in both varieties. Conversely, the growth and yield of linseed varieties were significantly restored by foliar spraying of α-tocopherol under saline conditions, improving shoot and root dry matter accumulation, photosynthetic pigment, mineral ion, proline, soluble protein contents, peroxidase, catalase, superoxide dismutase activities, and 100-seed weight. Moreover, foliar spray of α-tocopherol alleviated the effects of salinity stress by reducing the Na+ concentration and enhancing K+ and Ca2+ uptake. The Chandni variety performed better than the Roshni, for all growth and physiological parameters studied. Foliar spray of α-tocopherol (200mg L-1) alleviated salinity effects by improving the antioxidant potential of linseed varieties, which ultimately restored growth and yield. Therefore, the use of α-tocopherol may enhance the productivity of linseed and other crops under saline soils.
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ItemNo Preview AvailableThe occurrence of multidrug-resistant Mycobacterium tuberculosis from patients of pulmonary tuberculosis.(Journal of Infection in Developing Countries, 2022-04-30)INTRODUCTION: Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is one of the leading causes of death in the world. The resource constraints make it difficult to diagnose and monitor the cases of MDR-TB. GeneXpert is a recognized tool used to diagnose the patients of pulmonary tuberculosis in clinical settings across the globe. METHODOLOGY: The present one-year cross-sectional study was conducted to estimate the occurrence of MDR-TB in patients with pulmonary TB. A total of 1000 patients suspected of pulmonary tuberculosis were included in this study. A random convenient sampling technique was done to collect the sputum samples (twice) from the patients. Samples were processed for the detection of Mycobacterium tuberculosis using conventional detection methods like the Ziehl Nelson staining method and fluorescent microscopy. Additionally, Cepheid GeneXpert was used for molecular detection of MDR-TB in smear-positive samples of pulmonary tuberculosis by amplifying the rifampicin resistance determining region (RRDR; rpoB gene). All the tests were performed in the biosafety level III lab of District Headquarters Hospital Nankana Sahib. RESULTS: It was observed that 103 (10.3%) individuals were diagnosed as positive for tuberculosis among 1000 patients. Among these 103 TB positive cases, there were 11 (10.7%) patients diagnosed with rifampicin resistance gene (RR-Gene) of Mycobacterium tuberculosis. CONCLUSIONS: Overall findings of the study showed that MDR-TB is prevalent in pulmonary TB patients and GeneXpert is the most sensitive technique for early diagnosis of the disease, which may be very helpful in the treatment and control of this public health menace in low and middle-income countries.
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ItemCharacterisation of drug-resistant Mycobacterium tuberculosis mutations and transmission in Pakistan.(Springer Science and Business Media LLC, 2022-05-11)Tuberculosis, caused by Mycobacterium tuberculosis, is a high-burden disease in Pakistan, with multi-drug (MDR) and extensive-drug (XDR) resistance, complicating infection control. Whole genome sequencing (WGS) of M. tuberculosis is being used to infer lineages (strain-types), drug resistance mutations, and transmission patterns-all informing infection control and clinical decision making. Here we analyse WGS data on 535 M. tuberculosis isolates sourced across Pakistan between years 2003 and 2020, to understand the circulating strain-types and mutations related to 12 anti-TB drugs, as well as identify transmission clusters. Most isolates belonged to lineage 3 (n = 397; 74.2%) strain-types, and were MDR (n = 328; 61.3%) and (pre-)XDR (n = 113; 21.1%). By inferring close genomic relatedness between isolates (< 10-SNPs difference), there was evidence of M. tuberculosis transmission, with 55 clusters formed consisting of a total of 169 isolates. Three clusters consist of M. tuberculosis that are similar to isolates found outside of Pakistan. A genome-wide association analysis comparing 'transmitted' and 'non-transmitted' isolate groups, revealed the nusG gene as most significantly associated with a potential transmissible phenotype (P = 5.8 × 10-10). Overall, our study provides important insights into M. tuberculosis genetic diversity and transmission in Pakistan, including providing information on circulating drug resistance mutations for monitoring activities and clinical decision making.
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ItemNovel 1-Methyl-1H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity(American Chemical Society, 2019-03-15)A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure–activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.
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ItemGenetic variation within the genus Macropostrongyloides (Nematoda: Strongyloidea) from Australian macropodid and vombatid marsupials(CAMBRIDGE UNIV PRESS, 2019-11)The genetic variation and taxonomic status of the four morphologically-defined species of Macropostrongyloides in Australian macropodid and vombatid marsupials were examined using sequence data of the ITS+ region (=first and second internal transcribed spacers, and the 5.8S rRNA gene) of the nuclear ribosomal DNA. The results of the phylogenetic analyses revealed that Ma. baylisi was a species complex consisting of four genetically distinct groups, some of which are host-specific. In addition, Ma. lasiorhini in the common wombat (Vombatus ursinus) did not form a monophyletic clade with Ma. lasiorhini from the southern hairy-nosed wombat (Lasiorhinus latifrons), suggesting the possibility of cryptic (genetically distinct but morphologically similar) species. There was also some genetic divergence between Ma. dissimilis in swamp wallabies (Wallabia bicolor) from different geographical regions. In contrast, there was no genetic divergence among specimens of Ma. yamagutii across its broad geographical range or between host species (i.e. Macropus fuliginosus and M. giganteus). Macropostrongyloides dissimilis represented the sister taxon to Ma. baylisi, Ma. yamagutii and Ma. lasiorhini. Further morphological and molecular studies are required to assess the species complex of Ma. baylisi.
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ItemWorm burdens and associated histopathological changes caused by gastrointestinal nematodes in alpacas from Australia(Springer Verlag, 2019-03-14)In this study, 100 gastrointestinal tracts of Australian alpacas were examined to assess the worm burden and to identify the species of nematode present. Faecal samples were collected from 97 alpacas and processed for faecal egg counts (FECs). For identification of the species, both molecular (multiplexed-tandem polymerase chain reaction [MT-PCR]) and morphological techniques were used. Total worm counts (TWCs) revealed a mean burden of 1300 worms, with the highest burden of 29,000 worms. The average egg count was 501 eggs per gram of faeces (EPG), with the highest count of 3500 EPG. Nineteen different species of gastrointestinal nematodes (GINs) were identified, and Graphinema auchenia, Camelostrongylus mentulatus and Trichuris tenuis were recovered from Australian alpacas for the first time. Haemonchus contortus was the most prevalent nematode (81%) followed by C. mentulatus (60%). The majority of the nematodes found are shared with sheep, goats and cattle. Findings of this study provide useful insights into the spectrum of GINs and their burden in Australian alpacas.
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ItemEpidemiology of gastrointestinal nematodes of alpacas in Australia: II. A longitudinal study(SPRINGER, 2019-03)We conducted a longitudinal survey on 13 alpaca farms in four climatic zones of Australia to understand the epidemiology of gastrointestinal nematodes (GINs) of alpacas. A total of 1688 fresh faecal samples were collected from both sexes of alpacas from May 2015 to April 2016 and processed for faecal egg counts (FEC) and molecular identification of eggs using the multiplexed-tandem PCR assay. Based on egg morphology, the overall prevalence of GINs was 61% while that for strongyles was 53%. The overall mean FEC was 168 eggs per gram (EPG) of faeces, with the highest count of 15,540 EPG. Weaners had the highest prevalence (73%) and mean FEC (295 EPG) of GINs followed by tuis, crias and adults. Alpacas in the winter rainfall zone had the highest prevalence (68%) as well as FEC (266 EPG) followed by Mediterranean-type, non-seasonal and summer rainfall zones. Trichostrongylus spp. (83%, 89/107), Haemonchus spp. (71%, 76/107) and Camelostrongylus mentulatus (63%, 67/107) were the three most common GINs of alpacas across all climatic zones. The mixed-effects zero-inflated negative binomial regression model used in this study showed that it could help to design parasite control interventions targeted at both the herd level and the individual alpaca level. The findings of this study showed that the epidemiology of GINs of alpacas is very similar to those of cattle and sheep, and careful attention should be paid when designing control strategies for domestic ruminants co-grazing with alpacas.
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ItemEpidemiology of gastrointestinal nematodes of alpacas in Australia: I. A cross-sectional study(SPRINGER, 2019-03)This study involved a national cross-sectional survey of gastrointestinal nematodes (GINs) of alpacas in Australia. A total of 1545 fresh faecal samples were collected from both sexes of alpacas and processed for faecal egg counts (FEC) and molecular identification of nematodes using the multiplexed tandem PCR assay. Based on egg morphology, the overall prevalence of GINs was 66% while that for strongyles was 59%. The overall mean FEC was 276 eggs per gram (EPG) of faeces, with the highest count of 17,415 EPG. Male alpacas had a higher prevalence (68%, 334/490) as well as mean FEC (328 ± 60 EPG) of GINs than females (63%, 602/954; 227 ± 26, respectively). Weaners had the highest prevalence (80%) whereas tuis had the highest FEC (402 EPG) of nematodes. The highest prevalence (77%, 293/383) and FEC (630 EPG) of GINs were observed in the summer rainfall zone followed by the Mediterranean-type rainfall, non-seasonal rainfall and winter rainfall zones. The characterisation of nematode DNA isolated from faeces revealed the occurrence of seven different GINs, including Camelostrongylus mentulatus, Cooperia spp., Haemonchus spp., Oesophagostomum spp., Ostertagia ostertagi, Teladorsagia circumcincta and Trichostrongylus spp. Besides, Nematodirus spp. and Trichuris spp. were also found during FECs. The prevalence of Haemonchus spp. was highest in the summer rainfall zone while that of C. mentulatus was highest in the Mediterranean-type rainfall, non-seasonal rainfall and winter rainfall zones. The findings of this study revealed that alpacas harbour many of the same nematodes as sheep and cattle.