Transcriptomics of the racematic Praziquantel: R-PZQ versus S-PZQ in male Schistosoma mansoni
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ABSTRACT:
ORGANISM(S): Schistosoma mansoni
PROVIDER: GSE114506 | GEO | 2023/04/22
REPOSITORIES: GEO
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Project description:Schistosomiasis is a chronic neglected tropical disease caused by digenetic parasitic flatworms of the genus Schistosoma. The disease is estimated to affect over 206 million people, the majority of whom live in Africa where Schistosoma mansoni and Schistosoma japonicum are the major causative agents. While a number of drugs have been used to treat schistosomiasis, praziquantel (PZQ) is the only one that is widely available, relatively cheap, and easy to use. The reliance on a single drug for the treatment of such a prevalent disease is a cause for concern due to the potential for resistance to render PZQ ineffective. In this study we examine the transcriptome of three generations of a laboratory strain of S. mansoni (PR1) whose susceptibility to PZQ has been diminished across 9 passages through exposure to increasing sub-lethal doses of the drug. Miracidial susceptibility was significantly reduced after exposure to 2 x 50 mg/Kg PZQ during the first passage. Susceptibility of worms in vivo was first assessed during passage 5 when mice infected with PZQ-selected schistosomes were dosed with a lethal dose of 3 x 300 mg/Kg PZQ resulting in only a 10% reduction in worm number compared to control treatment. The emergence of reduced sensitivity was marked by a shift in sex ratio from a predominantly male to female population, a reduction in the length of females and ultimately the loss of the PZQ-selected line after passage 9, perhaps due to a selection induced fitness cost. Analysis of differentially regulated transcripts did not suggest that any particular gene product or pathway was associated with drug resistance suggesting either a loss of function mutation to a single gene or an epistatic interaction of multiple gene products.
2019-02-26 | GSE120682 | GEO
Project description:Background: Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel. Therefore, there is a pressing need to explore the effects of PZQ on the parasites at the molecular level and to pursue alternative and/or or synergistic drugs against schistosomiasis. Methodology: We used a custom-designed Schistosoma mansoni oligo-microarray to explore the effects of a sublethal dose of praziquantel on S. mansoni adult worms’ gene expression. We used functional analysis of gene interaction networks to identify differentially expressed genes that are known targets of other drugs already tested in humans for diverse disease conditions. Omeprazole, a proton pump inhibitor drug that is widely prescribed, was tested in combination with praziquantel. We comparatively assessed the efficacy of praziquantel or omeprazole alone and in combination against S. mansoni adult worms in vitro over a period of 120 hours. Principal Findings: We identified sets of genes that were affected by praziquantel on both paired and unpaired females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired females), indicating that the transcriptomics changes induced by praziquantel are heavily influenced by the mating status. We also identified genes that were similarly affected by praziquantel in males and females. The use of sublethal doses of praziquantel together with omeprazole showed a significantly enhanced worm mortality in vitro compared to praziquantel alone, thus evidencing a synergic effect. Conclusions: Functional analysis of gene interaction networks is an important approach to identify genes whose expression is affected by one drug and that are at the same time known targets of other drugs already tested in humans for diverse disease conditions, thus pointing the latter as possible synergic drugs. Combined treatment with omeprazol increases the efficacy of praziquantel against S. mansoni adult worms in vitro, and additional in vivo studies are warranted. Two-condition experiment, PZQ-treated vs. untreated . Biological replicates: 2 with dye-swap
2015-05-01 | E-GEOD-66697 | biostudies-arrayexpress
Project description:Background: Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel. Therefore, there is a pressing need to explore the effects of PZQ on the parasites at the molecular level and to pursue alternative and/or or synergistic drugs against schistosomiasis. Methodology: We used a custom-designed Schistosoma mansoni oligo-microarray to explore the effects of a sublethal dose of praziquantel on S. mansoni adult worms’ gene expression. We used functional analysis of gene interaction networks to identify differentially expressed genes that are known targets of other drugs already tested in humans for diverse disease conditions. Omeprazole, a proton pump inhibitor drug that is widely prescribed, was tested in combination with praziquantel. We comparatively assessed the efficacy of praziquantel or omeprazole alone and in combination against S. mansoni adult worms in vitro over a period of 120 hours. Principal Findings: We identified sets of genes that were affected by praziquantel on both paired and unpaired females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired females), indicating that the transcriptomics changes induced by praziquantel are heavily influenced by the mating status. We also identified genes that were similarly affected by praziquantel in males and females. The use of sublethal doses of praziquantel together with omeprazole showed a significantly enhanced worm mortality in vitro compared to praziquantel alone, thus evidencing a synergic effect. Conclusions: Functional analysis of gene interaction networks is an important approach to identify genes whose expression is affected by one drug and that are at the same time known targets of other drugs already tested in humans for diverse disease conditions, thus pointing the latter as possible synergic drugs. Combined treatment with omeprazol increases the efficacy of praziquantel against S. mansoni adult worms in vitro, and additional in vivo studies are warranted.
2015-05-01 | GSE66697 | GEO
Project description:Schistosoma mansoni is one of the most common etiological agents responsible for the disease schistosomiasis. More than 200 million people suffer from this disease making it the most severe tropical disease after malaria in terms of morbidity. Praziquantel (PZQ) is the treatment of choice for schistosomiasis and has been used almost exclusively to treat the disease since the 1970s. However, while the drug is lethal for sexually mature schistosomes, it is ineffective against juveniles. Thus, while morbidity can be eased, a cure is difficult to achieve. As a result there is an urgent need to develop a new generation of anti-schistosomal drugs, a task that will be made easier by understanding the mechanism of action of PZQ. As yet, neither the molecule to which PZQ binds nor the means by which it kills mature schistosomes is known. The overarching aim of this study was to understand the molecular basis of PZQ sensitivity in S. mansoni. We believe that juvenile worms survive PZQ treatment in vivo due to the induction of, as yet, unidentified protective molecular pathways. To address this hypothesis juvenile and adult PR1 S. mansoni were treated in vitro with sub-lethal concentrations of PZQ. mRNA was extracted from replicate samples, cRNA prepagreen and labeled with cyanine dyes for analysis using a 44K S. mansoni microarray. The data was then analyzed using Genespring. Our findings suggest that a number of genes associated with drug transport, iron homeostasis and apoptosis are induced in juvenile but not adult schistosomes and that this allows the juvenile worms to protect themselves against the lethal effects of PZQ long enough for the drug to be metabolized by the human host.
2011-05-27 | GSE29535 | GEO
Project description:Schistosoma mansoni is one of the most common etiological agents responsible for the disease schistosomiasis. More than 200 million people suffer from this disease making it the most severe tropical disease after malaria in terms of morbidity. Praziquantel (PZQ) is the treatment of choice for schistosomiasis and has been used almost exclusively to treat the disease since the 1970s. However, while the drug is lethal for sexually mature schistosomes, it is ineffective against juveniles. Thus, while morbidity can be eased, a cure is difficult to achieve. As a result there is an urgent need to develop a new generation of anti-schistosomal drugs, a task that will be made easier by understanding the mechanism of action of PZQ. As yet, neither the molecule to which PZQ binds nor the means by which it kills mature schistosomes is known. The overarching aim of this study was to understand the molecular basis of PZQ sensitivity in S. mansoni. We believe that juvenile worms survive PZQ treatment in vivo due to the induction of, as yet, unidentified protective molecular pathways. To address this hypothesis juvenile and adult PR1 S. mansoni were treated in vitro with sub-lethal concentrations of PZQ. mRNA was extracted from replicate samples, cRNA prepagreen and labeled with cyanine dyes for analysis using a 44K S. mansoni microarray. The data was then analyzed using Genespring. Our findings suggest that a number of genes associated with drug transport, iron homeostasis and apoptosis are induced in juvenile but not adult schistosomes and that this allows the juvenile worms to protect themselves against the lethal effects of PZQ long enough for the drug to be metabolized by the human host. 42 days post exposure (DPE) male schistosomes were exposed to 0 and 1 µg/mL praziquantel (PZQ) for 1 or 20 h and 10 µg/mL PZQ for 1 h. 42 DPE female schistosomes were exposed to 0, 1 and 10 µg/mL PZQ for 20 h. 28 DPE mixed-sex schistosomes were exposed to 0, 1 and 10 µg/mL PZQ for 1 and 20 h. All experiments were performed in biological triplicates. The 0 µg/mL PZQ exposures were used as controls to the appropriate groups and a universal reference was used in all experiments that was comprised of RNA derived from 100 mixed sex, unexposed 42 DPE schistosomes spiked with 0.5 % (v/v) RNA isolated from 42 DPE mixed sex worms exposed to 10 µg/mL PZQ, 0.5 % (v/v) RNA isolated from 28 DPE worms exposed to 10 µg/mL PZQ and 0.5 % (v/v) RNA isolated from 28 DPE worms unexposed to PZQ. Transcriptional response to praziquantel exposure by time and concentration
2011-05-27 | E-GEOD-29535 | biostudies-arrayexpress
Project description:Transcriptomics of the racematic Praziquantel: R-PZQ versus S-PZQ in male Schistosoma mansoni
| PRJNA471635 | ENA
Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of S. mansoni PR-1 to heat shock to confirm that while 6 week post infection (p.i.) schistosomes are sensitive to PZQ, 4 week p.i. schistosomes are not. Further, we have used this assay to demonstrate that this sensitivity develops between days 37 and 40 p.i. PZQ linked to the fluorophore BODIPY appears to easily enter the cells of intact 4 and 6 week p.i. schistosomes as well as mammalian NIH 3T3 cells and together, these data suggest that the differential effects of PZQ is not based on cell exclusion but probably due the differential expression of a target molecule at 6 weeks p.i. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress. Keywords: cell type comparison, time course
2008-11-10 | GSE12850 | GEO
Project description:Schistosomiasis is a disease caused by parasitic worms that significantly impacts on the lives of approximately 250 million people. During infection, female parasites release thousands of eggs, a significant number of which become trapped in the liver. The entrapment of the eggs triggers immune and inflammatory responses that in turn cause many of the health problems associated with the disease. In this study we analyzed the gene expression profiles of livers from mice infected with the human parasite Schistosoma mansoni over multiple time points, beginning when the parasites start to lay eggs. Mice were treated with a lethal dose of the anti-schistosomal drug praziquantel, and we identified a number of different genes and pathways that are central to immune and inflammatory responses that are active even in the absence of egg deposition. Praziquantel is the only drug available to treat schistosomiasis, however it is ineffective against juvenile parasites during the early stages of mammalian infection. We also show that the development of drug resistance may be due to the improved efficacy of the juvenile parasite to actively excrete the drug. These results provide insights into the effect of praziquantel on the host response to infection as well as ability of juvenile parasites to overcome the lethal effect of the drug.
2018-01-01 | GSE94132 | GEO
Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of S. mansoni PR-1 to heat shock to confirm that while 6 week post infection (p.i.) schistosomes are sensitive to PZQ, 4 week p.i. schistosomes are not. Further, we have used this assay to demonstrate that this sensitivity develops between days 37 and 40 p.i. PZQ linked to the fluorophore BODIPY appears to easily enter the cells of intact 4 and 6 week p.i. schistosomes as well as mammalian NIH 3T3 cells and together, these data suggest that the differential effects of PZQ is not based on cell exclusion but probably due the differential expression of a target molecule at 6 weeks p.i. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress. Keywords: cell type comparison, time course Cell type comparison: Four biologial replactes of schistosomes harvasted 4 and 6 week post-infection were performed. Time course: Four samples performed in duplicate for exposure to a sub-lethal dose of PZQ (50 M-BM-5g/ml) at time points 0, 30, 60, and 240 min over a common reference sample.
2008-11-10 | E-GEOD-12850 | biostudies-arrayexpress
Project description:Background: The parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel is still the only drug used for schistosomiasis treatment and reduction in drug efficiency has prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within S. mansoni gut is a major heme detoxification route involving lipid droplets in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of the antimalarial quinine (QN) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches. Methodology/Principal Findings: Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN (75mg/kg/day) from 11th to 17th day after infection decreased not only total, males and females worm burden (46.2 %-51.0 %), eggs production, but also the granulomatous reaction to parasite eggs trapped in the liver. These effects correlated with a significant impairment of Hz production (40%) specifically in S. mansoni females, being parallel to remarkable ultrastructural changes in female worms, particularly in the gut epithelium. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms. Conclusions: The overall significant reduction in several disease burden parameters by QN treatment indicates that interference of Hz formation in S. mansoni is a valid chemotherapeutical target for development of new antischistosomal drugs.
2009-07-13 | GSE14751 | GEO