Proteomic identification of galectin-11 and 14 ligands from Haemonchus contortus
- Sakthivel, Dhanasekaran, Swan, Jaclyn, Preston, Sarah, Shakif-Azam, MD, Faou, Pierre, Jiao, Yaqing, Downs, Rachael, Rajapaksha, Harinda, Gasser, Robin, Piedrafita, David, Beddoe, Travis
- Authors: Sakthivel, Dhanasekaran , Swan, Jaclyn , Preston, Sarah , Shakif-Azam, MD , Faou, Pierre , Jiao, Yaqing , Downs, Rachael , Rajapaksha, Harinda , Gasser, Robin , Piedrafita, David , Beddoe, Travis
- Date: 2018
- Type: Text , Journal article
- Relation: Peerj Vol. 6, no. 3 (2018), p. 1-19
- Full Text:
- Reviewed:
- Description: Haemonchus contortus is the most pathogenic nematode of small ruminants. Infection in sheep and goats results in anaemia that decreases animal productivity and can ultimately cause death. The involvement of ruminant-specific galectin-11 (LGALS-11) and galectin-14 (LGALS-14) has been postulated to play important roles in protective immune responses against parasitic infection; however, their ligands are unknown. In the current study, LGALS-11 and LGALS-14 ligands in H. contortus were identified from larval (L4) and adult parasitic stages extracts using immobilised LGALS-11 and LGALS-14 affinity column chromatography and mass spectrometry. Both LGALS-11 and LGALS-14 bound more putative protein targets in the adult stage of H. contortus (43 proteins) when compared to the larval stage (two proteins). Of the 43 proteins identified in the adult stage, 34 and 35 proteins were bound by LGALS-11 and LGALS-14, respectively, with 26 proteins binding to both galectins. Interestingly, hematophagous stage-specific sperm-coating protein and zinc metalloprotease (M13), which are known vaccine candidates, were identified as putative ligands of both LGALS-11 and LGALS- 14. The identification of glycoproteins of H. contortus by LGALS-11 and LGALS-14 provide new insights into host-parasite interactions and the potential for developing new interventions.
- Authors: Sakthivel, Dhanasekaran , Swan, Jaclyn , Preston, Sarah , Shakif-Azam, MD , Faou, Pierre , Jiao, Yaqing , Downs, Rachael , Rajapaksha, Harinda , Gasser, Robin , Piedrafita, David , Beddoe, Travis
- Date: 2018
- Type: Text , Journal article
- Relation: Peerj Vol. 6, no. 3 (2018), p. 1-19
- Full Text:
- Reviewed:
- Description: Haemonchus contortus is the most pathogenic nematode of small ruminants. Infection in sheep and goats results in anaemia that decreases animal productivity and can ultimately cause death. The involvement of ruminant-specific galectin-11 (LGALS-11) and galectin-14 (LGALS-14) has been postulated to play important roles in protective immune responses against parasitic infection; however, their ligands are unknown. In the current study, LGALS-11 and LGALS-14 ligands in H. contortus were identified from larval (L4) and adult parasitic stages extracts using immobilised LGALS-11 and LGALS-14 affinity column chromatography and mass spectrometry. Both LGALS-11 and LGALS-14 bound more putative protein targets in the adult stage of H. contortus (43 proteins) when compared to the larval stage (two proteins). Of the 43 proteins identified in the adult stage, 34 and 35 proteins were bound by LGALS-11 and LGALS-14, respectively, with 26 proteins binding to both galectins. Interestingly, hematophagous stage-specific sperm-coating protein and zinc metalloprotease (M13), which are known vaccine candidates, were identified as putative ligands of both LGALS-11 and LGALS- 14. The identification of glycoproteins of H. contortus by LGALS-11 and LGALS-14 provide new insights into host-parasite interactions and the potential for developing new interventions.
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus
- Jiao, Yaqing, Preston, Sarah, Song, Hongjian, Jabbar, Abdul, Liu, Yuxiu, Baell, Jonathan, Hofmann, Andreas, Hutchinson, Dana, Wang, Tao, Koehler, Anson, Fisher, Gillian, Andrews, Katherine, Laleu, Benoit, Palmer, Michael, Burrows, Jeremy, Wells, Timothy, Wang, Qingmin, Gasser, Robin
- Authors: Jiao, Yaqing , Preston, Sarah , Song, Hongjian , Jabbar, Abdul , Liu, Yuxiu , Baell, Jonathan , Hofmann, Andreas , Hutchinson, Dana , Wang, Tao , Koehler, Anson , Fisher, Gillian , Andrews, Katherine , Laleu, Benoit , Palmer, Michael , Burrows, Jeremy , Wells, Timothy , Wang, Qingmin , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: Parasites and Vectors Vol. 10, no. 1 (2017), p. 1-7
- Full Text:
- Reviewed:
- Description: Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus. © 2017 The Author(s).
- Authors: Jiao, Yaqing , Preston, Sarah , Song, Hongjian , Jabbar, Abdul , Liu, Yuxiu , Baell, Jonathan , Hofmann, Andreas , Hutchinson, Dana , Wang, Tao , Koehler, Anson , Fisher, Gillian , Andrews, Katherine , Laleu, Benoit , Palmer, Michael , Burrows, Jeremy , Wells, Timothy , Wang, Qingmin , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: Parasites and Vectors Vol. 10, no. 1 (2017), p. 1-7
- Full Text:
- Reviewed:
- Description: Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus. © 2017 The Author(s).
Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain
- Preston, Sarah, Korhonen, Pasi, Mouchiroud, Laurent, Cornaglia, Matteo, McGee, Sean, Young, Neil, Davis, Rohan, Crawford, Simon, Nowell, Cameron, Ansell, Brendan, Fisher, Gillian, Andrews, Katherine, Chang, Bill, Gijs, Martin, Sternberg, Paul, Auwerx, Johan, Baell, Jonathan, Hofmann, Andreas, Jabbar, Abdul, Gasser, Robin
- Authors: Preston, Sarah , Korhonen, Pasi , Mouchiroud, Laurent , Cornaglia, Matteo , McGee, Sean , Young, Neil , Davis, Rohan , Crawford, Simon , Nowell, Cameron , Ansell, Brendan , Fisher, Gillian , Andrews, Katherine , Chang, Bill , Gijs, Martin , Sternberg, Paul , Auwerx, Johan , Baell, Jonathan , Hofmann, Andreas , Jabbar, Abdul , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: FASEB Journal Vol. 31, no. 10 (2017), p. 4515-4532
- Full Text: false
- Reviewed:
- Description: 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. © FASEB.
- Herath, Dilrukshi, Preston, Sarah, Hofmann, Andreas, Davis, Rohan, Koehler, Anson, Chang, Bill, Jabbar, Abdul, Gasser, Robin
- Authors: Herath, Dilrukshi , Preston, Sarah , Hofmann, Andreas , Davis, Rohan , Koehler, Anson , Chang, Bill , Jabbar, Abdul , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: Veterinary Parasitology Vol. 244, no. (2017), p. 172-175
- Full Text: false
- Reviewed:
- Description: 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. © 2017 Elsevier B.V.
Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes
- Preston, Sarah, Jiao, Yaqing, Baell, Jonathan, Keiser, Jennifer, Crawford, Simon, Koehler, Anson, Wang, Tao, Simpson, Moana, Kaplan, Ray, Cowley, Karla, Simpson, Kaylene, Hofmann, Andreas, Jabbar, Abdul, Gasser, Robin
- Authors: Preston, Sarah , Jiao, Yaqing , Baell, Jonathan , Keiser, Jennifer , Crawford, Simon , Koehler, Anson , Wang, Tao , Simpson, Moana , Kaplan, Ray , Cowley, Karla , Simpson, Kaylene , Hofmann, Andreas , Jabbar, Abdul , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 7, no. 3 (2017), p. 286-294
- Full Text:
- Reviewed:
- Description: The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the ‘Open Scaffolds’ collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the ‘Open Scaffolds’ collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, “coiled” xL3 phenotype (IC50 = 3.46–5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31–12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3–50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50–100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets. © 2017 The Authors
- Authors: Preston, Sarah , Jiao, Yaqing , Baell, Jonathan , Keiser, Jennifer , Crawford, Simon , Koehler, Anson , Wang, Tao , Simpson, Moana , Kaplan, Ray , Cowley, Karla , Simpson, Kaylene , Hofmann, Andreas , Jabbar, Abdul , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 7, no. 3 (2017), p. 286-294
- Full Text:
- Reviewed:
- Description: The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the ‘Open Scaffolds’ collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the ‘Open Scaffolds’ collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, “coiled” xL3 phenotype (IC50 = 3.46–5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31–12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3–50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50–100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets. © 2017 The Authors
A perspective on genomic-guided anthelmintic discovery and repurposing using Haemonchus contortus
- Preston, Sarah, Jabbar, Abdul, Gasser, Robin
- Authors: Preston, Sarah , Jabbar, Abdul , Gasser, Robin
- Date: 2016
- Type: Text , Journal article
- Relation: Infection, Genetics and Evolution Vol. 40, no. (2016), p. 368-373
- Full Text: false
- Reviewed:
- Description: High-throughput molecular and computer technologies have become instrumental for systems biological explorations of parasites. Investigating the genomes and transcriptomes of different developmental stages of parasitic nematodes can provide insights into gene expression, regulation and function in the parasite, which is a significant step toward understanding their biology as well as host interactions and disease. This article covers aspects of a talk given at the MEEGID XII conference in Thailand in 2014. Here, we refer to recent studies of the genomes and transcriptomes of socioeconomically important parasitic nematodes of animals; provide an account of the barber's pole worm (Haemonchus contortus) and emerging drug resistance problems in this and related worms; we also propose a genomic-guided drug discovery and repurposing approach, involving the prediction of the druggable genome, prioritization of drug targets, screening of compound libraries against H. contortus and, briefly, a hit-to-lead optimization approach. We conclude by indicating prospects that molecular tool kits for nematodes provide to the scientific community for future comparative genomic, genetic, proteomic, metabolomic, evolutionary, biological, ecological and epidemiological investigations, and as a basis for biotechnological outcomes and translation. © 2015 Elsevier B.V.
Anthelmintic activity of selected ethno-medicinal plant extracts on parasitic stages of Haemonchus contortus
- Kumarasingha, Rasika, Preston, Sarah, Yeo, Tiong-Chia, Lim, Diana, Tu, Chu-Lee, Palombo, Enzo, Shaw, Jillian, Gasser, Robin, Boag, Peter
- Authors: Kumarasingha, Rasika , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Palombo, Enzo , Shaw, Jillian , Gasser, Robin , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: Parasites and Vectors Vol. 9, no. 1 (2016), p. 1-7
- Full Text:
- Reviewed:
- Description: Background: Parasitic roundworms (nematodes) cause substantial morbidity and mortality in livestock animals globally, and considerable productivity losses to farmers. The control of these nematodes has relied largely on the use of a limited number of anthelmintics. However, resistance to many of these these anthelmintics is now widespread, and, therefore, there is a need to find new drugs to ensure sustained and effective treatment and control into the future. Methods: Recently, we developed a screening assay to test natural, plant extracts with known inhibitory effects against the free-living worm Caenorhabditis elegans. Using this assay, we assessed here the effects of the extracts on motility and development of parasitic larval stages of Haemonchus contortus, one of the most important nematodes of small ruminants worldwide. Results: The study showed that two of five extracts from Picria fel-terrae Lour. have a significant inhibitory effect (at concentrations of 3-5 mg/ml) on the motility and development of H. contortus larvae. Although the two extracts originated from the same plant, they displayed different levels of inhibition on motility and development, which might relate to the presence of various active constituents in these extracts, or the same constituents at different concentrations in distinct parts of the plant. Conclusions: These results suggest that extracts from P. fel-terrae Lour. have promising anthelmintic activity and that more broadly, plant extracts are a potential rich source of anthelmintics to combat helminthic diseases. © 2016 Kumarasingha et al.
- Authors: Kumarasingha, Rasika , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Palombo, Enzo , Shaw, Jillian , Gasser, Robin , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: Parasites and Vectors Vol. 9, no. 1 (2016), p. 1-7
- Full Text:
- Reviewed:
- Description: Background: Parasitic roundworms (nematodes) cause substantial morbidity and mortality in livestock animals globally, and considerable productivity losses to farmers. The control of these nematodes has relied largely on the use of a limited number of anthelmintics. However, resistance to many of these these anthelmintics is now widespread, and, therefore, there is a need to find new drugs to ensure sustained and effective treatment and control into the future. Methods: Recently, we developed a screening assay to test natural, plant extracts with known inhibitory effects against the free-living worm Caenorhabditis elegans. Using this assay, we assessed here the effects of the extracts on motility and development of parasitic larval stages of Haemonchus contortus, one of the most important nematodes of small ruminants worldwide. Results: The study showed that two of five extracts from Picria fel-terrae Lour. have a significant inhibitory effect (at concentrations of 3-5 mg/ml) on the motility and development of H. contortus larvae. Although the two extracts originated from the same plant, they displayed different levels of inhibition on motility and development, which might relate to the presence of various active constituents in these extracts, or the same constituents at different concentrations in distinct parts of the plant. Conclusions: These results suggest that extracts from P. fel-terrae Lour. have promising anthelmintic activity and that more broadly, plant extracts are a potential rich source of anthelmintics to combat helminthic diseases. © 2016 Kumarasingha et al.
Metabolic profiling and in vitro assessment of anthelmintic fractions of Picria fel-terrae Lour
- Kumarasingha, Rasika, Karpe, Avinash, Preston, Sarah, Yeo, Tiong-Chia, Lim, Diana, Tu, Chu-Lee, Luu, Jennii, Simpson, Kaylene, Shaw, Jillian, Gasser, Robin, Beale, David, Morrison, Paul, Palombo, Enzo, Boag, Peter
- Authors: Kumarasingha, Rasika , Karpe, Avinash , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Luu, Jennii , Simpson, Kaylene , Shaw, Jillian , Gasser, Robin , Beale, David , Morrison, Paul , Palombo, Enzo , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 6, no. 3 (2016), p. 171-178
- Full Text:
- Reviewed:
- Description: Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented. Image 1 •Chemical fractionation of Picria fel-terrae Lour. plant extract.•Anthelmintic activity against Caenorhabditis elegans and Haemonchus contortus.•Metabolic profiling and chemometric analysis of active fraction.•Active fraction has minimal mammalian cytotoxicity.
- Authors: Kumarasingha, Rasika , Karpe, Avinash , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Luu, Jennii , Simpson, Kaylene , Shaw, Jillian , Gasser, Robin , Beale, David , Morrison, Paul , Palombo, Enzo , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 6, no. 3 (2016), p. 171-178
- Full Text:
- Reviewed:
- Description: Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented. Image 1 •Chemical fractionation of Picria fel-terrae Lour. plant extract.•Anthelmintic activity against Caenorhabditis elegans and Haemonchus contortus.•Metabolic profiling and chemometric analysis of active fraction.•Active fraction has minimal mammalian cytotoxicity.
- Preston, Sarah, Luo, Junjie, Zhang, Yuezhou, Jabbar, Abdul, Crawford, Simon, Baell, Jonathan, Hofmann, Andreas, Hu, Min, Zhou, Hai-Bing, Gasser, Robin
- Authors: Preston, Sarah , Luo, Junjie , Zhang, Yuezhou , Jabbar, Abdul , Crawford, Simon , Baell, Jonathan , Hofmann, Andreas , Hu, Min , Zhou, Hai-Bing , Gasser, Robin
- Date: 2016
- Type: Text , Journal article
- Relation: Parasites & Vectors Vol. 9, no. 1 (2016), p. 346
- Full Text: false
- Reviewed:
- Description: Parasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites.
- Preston, Sarah, Beddoe, Travis, Walkden-Brown, Stephen, Meeusen, Els, Piedrafita, David
- Authors: Preston, Sarah , Beddoe, Travis , Walkden-Brown, Stephen , Meeusen, Els , Piedrafita, David
- Date: 2015
- Type: Text , Journal article
- Relation: International Journal for Parasitology Vol. 45, no. 12 (2015), p. 791-796
- Full Text: false
- Reviewed:
- Description: Galectin-11 is released from epithelial cells of the gastrointestinal tract, specifically following infection with gastrointestinal parasites including the highly pathogenic nematode, Haemonchus contortus. The function(s) of galectin-11 are currently unknown but seem to be associated with the development of immunity by the host. The aim of the present study was to examine the interaction of galectin-11 with the different parasitic life cycle stages of H. contortus and determine any effects on parasite development. The results of this study showed that galectin-11 binds to the surface of the L4 and adult stages of the parasite but not to the exsheathed L3 stage. In addition, at a lower concentration, binding to the L4 was specifically localised to the pharynx region. Subsequent in vitro assays demonstrated significant inhibition of larval growth and development in the presence of recombinant galectin-11. These results indicate, to our knowledge for the first time, a functional role for galectin-11 in gastrointestinal nematode infection of ruminants and a mechanism of action of galectin-11, targeting the development and growth of the L4 and possibly the adult parasite stage. © 2015 .
Low cost whole-organism screening of compounds for anthelmintic activity
- Preston, Sarah, Jabbar, Abdul, Nowell, Cameron, Joachim, Anja, Ruttkowski, Barbel, Baell, Jonathan, Cardno, Tony, Korhonen, Pasi, Piedrafita, David, Ansell, Brendan, Jex, Aaron, Hofmann, Andreas, Gasser, Robin
- Authors: Preston, Sarah , Jabbar, Abdul , Nowell, Cameron , Joachim, Anja , Ruttkowski, Barbel , Baell, Jonathan , Cardno, Tony , Korhonen, Pasi , Piedrafita, David , Ansell, Brendan , Jex, Aaron , Hofmann, Andreas , Gasser, Robin
- Date: 2015
- Type: Text , Journal article
- Relation: International Journal for Parasitology Vol. 45, no. 5 (2015), p. 333-343
- Full Text: false
- Reviewed:
- Description: Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-α]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47μM. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (
Current status for gastrointestinal nematode diagnosis in small ruminants: where are we and where are we going?
- Preston, Sarah, Sandeman, Mark, Gonzalez, Jorge, Piedrafita, David
- Authors: Preston, Sarah , Sandeman, Mark , Gonzalez, Jorge , Piedrafita, David
- Date: 2014
- Type: Text , Journal article
- Relation: Journal of immunology research Vol. 2014, no. September (2014), p. Article no. 210350
- Full Text:
- Reviewed:
- Description: Gastrointestinal nematode (GIN) parasites pose a significant economic burden particularly in small ruminant production systems. Anthelmintic resistance is a serious concern to the effective control of GIN parasites and has fuelled the focus to design and promote sustainable control of practices of parasite control. Many facets of sustainable GIN parasite control programs rely on the ability to diagnose infection both qualitatively and quantitatively. Diagnostics are required to determine anthelmintic efficacies, for targeted treatment programs and selection of animals for parasite resistant breeding. This review describes much of the research investigated to date to improve the current diagnostic for the above practices which is based on counting the number of parasite eggs in faeces.
- Authors: Preston, Sarah , Sandeman, Mark , Gonzalez, Jorge , Piedrafita, David
- Date: 2014
- Type: Text , Journal article
- Relation: Journal of immunology research Vol. 2014, no. September (2014), p. Article no. 210350
- Full Text:
- Reviewed:
- Description: Gastrointestinal nematode (GIN) parasites pose a significant economic burden particularly in small ruminant production systems. Anthelmintic resistance is a serious concern to the effective control of GIN parasites and has fuelled the focus to design and promote sustainable control of practices of parasite control. Many facets of sustainable GIN parasite control programs rely on the ability to diagnose infection both qualitatively and quantitatively. Diagnostics are required to determine anthelmintic efficacies, for targeted treatment programs and selection of animals for parasite resistant breeding. This review describes much of the research investigated to date to improve the current diagnostic for the above practices which is based on counting the number of parasite eggs in faeces.
Evaluation of the role of galectins in parasite immunity
- Preston, Sarah, Dunphy, Jillian, Beddoe, Travis, Meeusen, Els, Young, Anna
- Authors: Preston, Sarah , Dunphy, Jillian , Beddoe, Travis , Meeusen, Els , Young, Anna
- Date: 2014
- Type: Text , Book chapter
- Relation: Galectins: Methods and Protocols (Methods in Molecular Biology series) Chapter 25 p. 371-395
- Full Text: false
- Reviewed:
- Description: Galectin-11 and galectin-14 are ruminant galectins involved in parasitic infections. Although their roles in parasite immunity are still being elucidated, its appears that their functions are parasite specific. In gastrointestinal infections with the nematode Haemonchus contortus, both galectin-11 and galectin-14 appear to be protective. However, in a chronic infection of liver fluke, Fasciola hepatica, these galectins may aid parasite survival. This chapter discusses the methods designed to study parasitic infections in sheep, which have provided us with insight into the functions of galectin-11 and galectin-14 during host–parasite interactions. These methods include parasite cultivation and infection, galectin staining of host and parasite tissue, surface staining of parasites with recombinant galectins and in vitro assays to monitor the effect of galectins on larval development. © Springer Science+Business Media New York 2015.
The effect of different adjuvants on immune parameters and protection following vaccination of sheep with a larval-specific antigen of the gastrointestinal nematode, Haemonchus contortus
- Piedrafita, David, Preston, Sarah, Kemp, Joanna, De Veer, Michael, Sherrard, Jayne, Kraska, Troy, Elhay, Martin, Meeusen, Els
- Authors: Piedrafita, David , Preston, Sarah , Kemp, Joanna , De Veer, Michael , Sherrard, Jayne , Kraska, Troy , Elhay, Martin , Meeusen, Els
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE. Vol. 8, no. 10, (Art. no.e78357) (2013), p. 1-8
- Full Text:
- Reviewed:
- Description: It has recently been recognised that vaccine adjuvants play a critical role in directing the nature of a vaccine induced effector response. In the present study, several adjuvants were evaluated for their ability to protect sheep after field vaccination with the larval-specific Haemonchus contortus antigen, HcsL3. Using a suboptimal antigen dose, aluminium adjuvant was shown to reduce the cumulative faecal egg counts (cFEC) and worm burden by 23% and 25% respectively, in agreement with a previous study. The addition of Quil A to the aluminium-adjuvanted vaccine brought cFEC back to control levels. Vaccination with the adjuvant DEAE-dextran almost doubled the protection compared to the aluminium-adjuvanted vaccine resulting in 40% and 41% reduction in cFEC and worm counts compared to controls. Examination of skin responses following i.d. injection of exsheathed L3, revealed that cFEC was negatively correlated with wheal size and tissue eosinophils for the DEAE-dextran and aluminium-adjuvanted groups respectively. These studies have for the first time shown the potential of DEAE-dextran adjuvant for helminth vaccines, and discovered significant cellular correlates of vaccine-induced protection. Funding: Australian Research Council Linkage grant LP0668945 and the ARC-Centre of Excellence in Structural and Functional Microbial Genomics. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip
- Authors: Piedrafita, David , Preston, Sarah , Kemp, Joanna , De Veer, Michael , Sherrard, Jayne , Kraska, Troy , Elhay, Martin , Meeusen, Els
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE. Vol. 8, no. 10, (Art. no.e78357) (2013), p. 1-8
- Full Text:
- Reviewed:
- Description: It has recently been recognised that vaccine adjuvants play a critical role in directing the nature of a vaccine induced effector response. In the present study, several adjuvants were evaluated for their ability to protect sheep after field vaccination with the larval-specific Haemonchus contortus antigen, HcsL3. Using a suboptimal antigen dose, aluminium adjuvant was shown to reduce the cumulative faecal egg counts (cFEC) and worm burden by 23% and 25% respectively, in agreement with a previous study. The addition of Quil A to the aluminium-adjuvanted vaccine brought cFEC back to control levels. Vaccination with the adjuvant DEAE-dextran almost doubled the protection compared to the aluminium-adjuvanted vaccine resulting in 40% and 41% reduction in cFEC and worm counts compared to controls. Examination of skin responses following i.d. injection of exsheathed L3, revealed that cFEC was negatively correlated with wheal size and tissue eosinophils for the DEAE-dextran and aluminium-adjuvanted groups respectively. These studies have for the first time shown the potential of DEAE-dextran adjuvant for helminth vaccines, and discovered significant cellular correlates of vaccine-induced protection. Funding: Australian Research Council Linkage grant LP0668945 and the ARC-Centre of Excellence in Structural and Functional Microbial Genomics. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip