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Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni.

ABSTRACT: Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing an important economic burden. The schistosomicides hycanthone, and its later proxy oxamniquine, were widely used for treatments in endemic areas during the twentieth century. Recently, the mechanism of action, as well as the genetic origin of a stably and Mendelian inherited resistance for both drugs was elucidated in two strains. However, several observations suggested early on that alternative mechanisms might exist, by which resistance could be induced for these two drugs in sensitive lines of schistosomes. This induced resistance appeared rapidly, within the first generation, but was metastable (not stably inherited). Epigenetic inheritance could explain such a phenomenon and we therefore re-analyzed the historical data with our current knowledge of epigenetics. In addition, we performed new experiments such as ChIP-seq on hycanthone treated worms. We found distinct chromatin structure changes between sensitive worms and induced resistant worms from the same strain. No specific pathway was discovered, but genes in which chromatin structure modifications were observed are mostly associated with transport and catabolism, which makes sense in the context of the elimination of the drug. Specific differences were observed in the repetitive compartment of the genome. We finally describe what types of experiments are needed to understand the complexity of heritability that can be based on genetic and/or epigenetic mechanisms for drug resistance in schistosomes.

SUBMITTER: Roquis D

PROVIDER: S-EPMC4099960 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Chromatin structural changes around satellite repeats on the female sex chromosome in Schistosoma mansoni and their possible role in sex chromosome emergence.

Project description:BACKGROUND: In the leuphotrochozoan parasitic platyhelminth Schistosoma mansoni, male individuals are homogametic (ZZ) whereas females are heterogametic (ZW). To elucidate the mechanisms that led to the emergence of sex chromosomes, we compared the genomic sequence and the chromatin structure of male and female individuals. As for many eukaryotes, the lower estimate for the repeat content is 40%, with an unknown proportion of domesticated repeats. We used massive sequencing to de novo assemble all repeats, and identify unambiguously Z-specific, W-specific and pseudoautosomal regions of the S. mansoni sex chromosomes. RESULTS: We show that 70 to 90% of S. mansoni W and Z are pseudoautosomal. No female-specific gene could be identified. Instead, the W-specific region is composed almost entirely of 36 satellite repeat families, of which 33 were previously unknown. Transcription and chromatin status of female-specific repeats are stage-specific: for those repeats that are transcribed, transcription is restricted to the larval stages lacking sexual dimorphism. In contrast, in the sexually dimorphic adult stage of the life cycle, no transcription occurs. In addition, the euchromatic character of histone modifications around the W-specific repeats decreases during the life cycle. Recombination repression occurs in this region even if homologous sequences are present on both the Z and W chromosomes. CONCLUSION: Our study provides for the first time evidence for the hypothesis that, at least in organisms with a ZW type of sex chromosomes, repeat-induced chromatin structure changes could indeed be the initial event in sex chromosome emergence.

| S-EPMC3701142 | biostudies-literature

Dosage Compensation throughout the Schistosoma mansoni Lifecycle: Specific Chromatin Landscape of the Z Chromosome.

Project description:Differentiated sex chromosomes are accompanied by a difference in gene dose between X/Z-specific and autosomal genes. At the transcriptomic level, these sex-linked genes can lead to expression imbalance, or gene dosage can be compensated by epigenetic mechanisms and results into expression level equalization. Schistosoma mansoni has been previously described as a ZW species (i.e., female heterogamety, in opposition to XY male heterogametic species) with a partial dosage compensation, but underlying mechanisms are still unexplored. Here, we combine transcriptomic (RNA-Seq) and epigenetic data (ChIP-Seq against H3K4me3, H3K27me3, and H4K20me1 histone marks) in free larval cercariae and intravertebrate parasitic stages. For the first time, we describe differences in dosage compensation status in ZW females, depending on the parasitic status: free cercariae display global dosage compensation, whereas intravertebrate stages show a partial dosage compensation. We also highlight regional differences of gene expression along the Z chromosome in cercariae, but not in the intravertebrate stages. Finally, we feature a consistent permissive chromatin landscape of the Z chromosome in both sexes and stages. We argue that dosage compensation in schistosomes is characterized by chromatin remodeling mechanisms in the Z-specific region.

| S-EPMC6628874 | biostudies-literature

Distinct Schistosoma mansoni-Specific Immunoglobulin Subclasses Are Induced by Different Schistosoma mansoni Stages-A Tool to Decipher Schistosoma mansoni Infection Stages.

Project description:Despite the existence of an effective medication against schistosomiasis, the disease remains a major health problem in affected areas, especially for those lacking appropriate sanitary facilities. Moreover, treatment cannot prevent re-infection since it is only effective on adult schistosome worms. Previous retrospective studies in the Sudan have discovered unique immuno-epidemiological profiles in uninfected individuals and those positive for Schistosoma mansoni via polymerase chain reaction (PCR) but egg-negative and those with eggs in their stool. Expanding on these data, serum samples from these individuals were further investigated for the presence of cercarial (SmCTF)-specific antibodies, which would indicate immune responses at the early stages of infection. Indeed, SmCTF IgG1, 2, 3 and 4 levels were significantly elevated in SmPCR+ individuals when compared to egg+ patients. Following multivariable regression analysis, including SmCTF-specific Igs, Schistosoma egg antigen (SEA)-specific and Schistosoma worm antigen (SWA)-specific immunoglobulins revealed a specific immunoglobulin (Ig) profile of individuals presenting different states of infection, which may be a useful future tool in order to identify egg- individuals and thereby prevent unnecessary treatments.

| S-EPMC8778779 | biostudies-literature

Drug-induced exposure of Schistosoma mansoni antigens SmCD59a and SmKK7.

Project description:BackgroundSchistosomiasis is a serious health problem especially in developing countries and affects more than 243 million people. Only few anthelmintic drugs are available up to now. A major obstacle for drug treatment is the different developmental stages and the varying host compartments during worm development. Anthelmintic drugs have been tested mainly on adult schistosomes or freshly transformed cercariae. Knowledge concerning the larval stages is lacking.Methodology/principal findingsIn this study, we used in vitro-grown schistosomula (aged between 2 to 14 days) to investigate drug effects of the three anthelmintics praziquantel, artemether, and oxamniquine. Further, we analyzed the antibody accessibility of two exemplary schistosome antigens SmCD59a and SmKK7, before and after drug treatment. Our results demonstrated that praziquantel applied at a concentration of 1 μM inhibited development of all life stages. Application of 10 μM praziquantel led to dramatic morphological changes of all schistosomula. Artemether at 1 and 10 μM had differential effects depending on whether it was applied to 2-day as compared to 7- and 14-day schistosomula. While 2-day schistosomula were not killed but inhibited from further development, severe morphological damage was seen in 7- and 14-day schistosomula. Oxamniquine (1 and 10 μM) led to severe morphological impairment in all life stages. Analyzing the accessibility of the antigens SmCD59a and SmKK7 before drug treatment showed no antibody binding on living intact schistosomula. However, when schistosomula were treated with anthelmintics, both antigens became exposed on the larvae. Oxamniquine turned out to be most effective in promoting antibody binding to all schistosomula stages.ConclusionThis study has revealed marked differences in anthelmintic drug effects against larvae. Drug treatment increases surface antigen presentation and renders larvae accessible to antibody attack.

| S-EPMC4361651 | biostudies-literature

Schistosoma mansoni-specific immune responses and allergy in Uganda.

Project description:Low allergy-related disease (ARD) prevalence in low-income countries may be partly attributed to helminth infections. In the Schistosoma mansoni (Sm)-endemic Lake Victoria islands (Uganda), we recently observed positive helminth-allergy associations, despite low ARD prevalence. To understand how Sm-induced cytokine and antibody profiles might influence allergic response profiles in this population, we assessed Schistosoma worm (SWA)- and egg antigen (SEA)-specific Th1 (IFN-γ), Th2 (IL-5, IL-13) and regulatory (IL-10) cytokine profiles (n = 407), and total (n = 471), SWA-, SEA- and allergen (house dust mite [HDM] and cockroach)-specific (as)IgE and IgG4 profiles (n = 2117) by ELISA. Wheeze was inversely associated with SWA-specific IFN-γ (P < .001) and IL-10 (P = .058), and SEA-specific IL-5 (P = .004). Conversely, having a detectable asIgE response was positively associated with SWA-specific IL-5 (P = .006) and IL-10 (P < .001). Total, SWA-, SEA- and allergen-specific IgE and IgG4 responses were higher among Sm Kato-Katz positive (SmKK+) and skin prick test (SPT)+ individuals compared to SmKK- and SPT- individuals. However, total and asIgG4/IgE ratios were lower among SPT+ and wheezing individuals. We conclude that, in this population, helminth-induced antibody and cytokine responses may underlie individual positive helminth-atopy associations, while the overall IgG4-IgE balance may contribute to the low overall prevalence of clinical allergies in such settings.

| S-EPMC5767746 | biostudies-literature

Prototypic chromatin insulator cHS4 protects retroviral transgene from silencing in Schistosoma mansoni.

Project description:Vesicular stomatitis virus glycoprotein (VSVG) pseudotyped murine leukemia virus (MLV) virions can transduce schistosomes, leading to chromosomal integration of reporter transgenes. To develop VSVG-MLV for functional genomics in schistosomes, the influence of the chicken ?-globin cHS4 element, a prototypic chromatin insulator, on transgene expression was examined. Plasmid pLNHX encoding the MLV 5'- and 3'-Long Terminal Repeats flanking the neomycin phosphotransferase gene (neo) was modified to include, within the U3 region of the 3'-LTR, active components of cHS4 insulator, the 250 bp core fused to the 400 bp 3'-region. Cultured larvae of Schistosoma mansoni were transduced with virions from producer cells transfected with control or cHS4-bearing plasmids. Schistosomules transduced with cHS4 virions expressed 2-20 times higher levels of neo than controls, while carrying comparable numbers of integrated proviral transgenes. The findings not only demonstrated that cHS4 was active in schistosomes but also they represent the first report of activity of cHS4 in any Lophotrochozoan species, which has significant implications for evolutionary conservation of heterochromatin regulation. The findings advance prospects for transgenesis in functional genomics of the schistosome genome to discover intervention targets because they provide the means to enhance and extend transgene activity including for vector based RNA interference.

| S-EPMC3288229 | biostudies-literature

Effect of Agrochemical Exposure on Schistosoma mansoni Cercariae Survival and Activity.

Project description:Singular use of activity assays or staining dyes to assess pathogen agrochemical tolerance can underestimate tolerance if pesticides cause sublethal effects. We exposed Schistosoma mansoni cercariae, the aquatic life stage of this trematode that infects humans, to 4 insecticides at 5 concentrations using a 24-h time-to-death assay. We used Trypan blue dye, which stains dead tissue, and activity assays simultaneously to discriminate dead from live but paralyzed individuals. Whereas cypermethrin, deltamethrin, and dimethoate exposure did not affect cercariae at any ecologically relevant concentrations, methamidophos exposure increased survival of cercariae compared with those in the controls. This was because methamidophos-induced paralysis reduced cercarial activity and thus energy expenditures, extending the lifespan of this short-lived parasite that causes human schistosomiasis. These findings highlight that sublethal effects should be considered when pesticide effects on disease are under investigation. Environ Toxicol Chem 2020;39:1421-1428. © 2020 SETAC.

| S-EPMC8569529 | biostudies-literature

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Project description:Interference of hemozoin formation in Schistosoma mansoni by quinine reduces experimental schistosomiasis

| PRJNA112241 | ENA

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Project description:An EST project for Schistosoma mansoni

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Project description:Combinatory microarray and SuperSAGE analyses identify pairing-dependently transcribed genes in Schistosoma mansoni males, such as follistatin [Microarray]

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