Female biased sex-ratio in Schistosoma mansoni after exposure to an allopatric intermediate host strain of Biomphalaria glabrata.

International audience: For parasites that require multiple hosts to complete their development, the interaction with the intermediate host may have an impact on parasite transmission and development in the definitive host. The human parasite Schistosoma mansoni needs two different hosts to complete its life cycle: the freshwater snail Biomphalaria glabrata (in South America) as intermediate host and a human or rodents as final host. To investigate the influence of the host environment on life history traits in the absence of selection, we performed experimental infections of two B. glabrata strains of different geographic origin with the same clonal population of S. mansoni. One B. glabrata strain is the sympatric host and the other one the allopatric host. We measured prevalence in the snail, the cercarial infectivity, sex-ratio, immunopathology in the final host and microsatellite frequencies of individual larvae in three successive generations. We show that, even if the parasite population is clonal based on neutral markers, S. mansoni keeps the capacity of generating phenotypic plasticity and/or variability for different life history traits when confront to an unusual environment, in this study the intermediate host. The most dramatic change was observed in sex-ratio: in average 1.7 times more female cercariae were produced when the parasite developed in an allopatric intermediate host

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

International audienceSchistosoma 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 schistosome

Chemical Ordering in Bimetallic FeCo Nanoparticles: From a Direct Chemical Synthesis to Application As Efficient High-Frequency Magnetic Material

Single-crystalline FeCo nanoparticles with tunable size and shape were prepared by co-decomposing two metal-amide precursors under mild conditions. The nature of the ligands introduced in this organometallic synthesis drastically affects the reactivity of the precursors and, thus, the chemical distribution within the nanoparticles. The presence of the B2 short-range order was evidenced in FeCo nanoparticles prepared in the presence of HDAHCl ligands, combining 57 Fe Mössbauer, zero-field 59 Co ferromagnetic nuclear resonance (FNR), and X-ray diffraction studies. This is the first time that the B2 structure is directly formed during synthesis without the need of any annealing step. The as-prepared nanoparticles exhibit magnetic properties comparable with the ones for the bulk (M s = 226 Am 2 ·kg -1 ). Composite magnetic materials prepared from these FeCo nanoparticles led to a successful proof-of-concept of the integration on inductor-based filters (27% enhancement of the inductance value at 100 MHz)

Antitumour necrosis factor-α therapy for hidradenitis suppurativa: results from a national cohort study between 2000 and 2013

International audienceHidradenitis suppurativa (HS) is a frequent chronic inflammatory skin disease typically characterized by recurrent painful, deep inflammatory nodules of the axillary, breast, groin and gluteal areas. European recommendations are mainly based on expert opinion. Drug treatments are heterogenous (e.g., antibiotics, corticosteroids, retinoids) and lack consensus among expert centres. The most severe disease forms or those failing to respond to conventional drugs may be associated with worsened functional prognosis. Anti-tumor necrosis factor α (anti-TNFα) drugs have been prescribed in these cases. The results of randomized controlled trials (RCTs) are discordant. Three RCTs concluded to the efficacy of adalimumab (ADA), and two others did not detect any difference between infliximab (IFX) or etanercept (ETA) and placebo. Finally, data from the literature and reported experiences do not conclude on the efficacy of anti-TNFα drugs for HS. This article is protected by copyright. All rights reserve

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

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.Keywords: Evolution, Dicer, Biomphalaria glabrata, Heterochromatin, Separate sexes, Argonaute Proteins, Y chromosomes, Genome, Repetitive DNA, Methylatio

The Epigenome of Schistosoma mansoni Provides Insight about How Cercariae Poise Transcription until Infection

Background: Chromatin structure can control gene expression and can define specific transcription states. For example, bivalent methylation of histone H3K4 and H3K27 is linked to poised transcription in vertebrate embryonic stem cells (ESC). It allows them to rapidly engage specific developmental pathways. We reasoned that non-vertebrate metazoans that encounter a similar developmental constraint (i.e. to quickly start development into a new phenotype) might use a similar system. Schistosomes are parasitic platyhelminthes that are characterized by passage through two hosts: a mollusk as intermediate host and humans or rodents as definitive host. During its development, the parasite undergoes drastic changes, most notable immediately after infection of the definitive host, i.e. during the transition from the free-swimming cercariae into adult worms. Methodology/Principal Findings: We used Chromatin Immunoprecipitation followed by massive parallel sequencing (ChIP-Seq) to analyze genome-wide chromatin structure of S. mansoni on the level of histone modifications (H3K4me3, H3K27me3, H3K9me3, and H3K9ac) in cercariae, schistosomula and adults (available at http://genome.univ-perp.fr). We saw striking differences in chromatin structure between the developmental stages, but most importantly we found that cercariae possess a specific combination of marks at the transcription start sites (TSS) that has similarities to a structure found in ESC. We demonstrate that in cercariae no transcription occurs, and we provide evidences that cercariae do not possess large numbers of canonical stem cells. Conclusions/Significance: We describe here a broad view on the epigenome of a metazoan parasite. Most notably, we find bivalent histone H3 methylation in cercariae. Methylation of H3K27 is removed during transformation into schistosomula (and stays absent in adults) and transcription is activated. In addition, shifts of H3K9 methylation and acetylation occur towards upstream and downstream of the transcriptional start site (TSS). We conclude that specific H3 modifications are a phylogenetically older and probably more general mechanism, i.e. not restricted to stem cells, to poise transcription. Since adult couples must form to cause the disease symptoms, changes in histone modifications appear to be crucial for pathogenesis and represent therefore a therapeutic target. Author Summary: The blood fluke Schistosoma mansoni causes intestinal bilharzia. The parasite has a complex life cycle in which a freshwater snail serves as intermediate host from which the human infecting larvae hatch. These larvae will actively seek skin contact, penetrate through the epithelium and start developing straight away into adult worms. Development from larvae into adults needs thorough adjustment of gene expression through repositioning or modification of proteins that are associated with DNA (the chromatin). We decided to compare the chromatin of human infective larvae (cercariae), the first developmental stage after infection of the vertebrate host (schistosomula) and adults of S. mansoni. We found that cercariae possess chromatin structures (modifications of histone H3) around the beginning of genes that are very different from schistosomula and adults. We conclude that this structure serves to keep gene transcription in a poised state, i.e. transcription is initiated and can start immediately when the blocking histone modification is removed. A similar type of histone modification was found in embryonic stem cells of vertebrates and our data indicate that it is either a more ancient and/or more general means to poise transcription than previously assumed. Since many parasites possess infective stages that develop rapidly within the host, this particular chromatin structure could be a therapeutic target for a new class of antiparasitic drugs

Étude de la variabilité phénotypique, sous influence environnementale, chez S. mansoni, parasite de l'homme :implication de l'épigénome par une approche globale

The bilharziasis is a human parasitic disease which is in the second world rank, after the malaria, in terms of morbidity and mortality inferred by the parasite. More than 200 million people are infested in 74 countries and more than 200 000 people die a year (Chitsulo and al. 2004; Gryseels and al. 2006). Schistosoma mansoni, here studied, is responsible for the intestinal bilharziasis. This parasite possesses a complex life cycle, getting through necessarily two hosts: an intermediate host mollusk of fresh water and a human definitive host or murin. During the cycle of development, the various stages are exposed to diverse environments. For example, the embryonic stages can be confronted with several intermediate hosts (origin of mollusk) or definitive (human being or murin). My thesis research concerns the influence of the environment on the épigénome of Schistosoma mansoni. The epigenetic information is an additional source for the creation of variants phenotypic, we propose that some of these variants can be inherited and selected, and so confer an advantage to the parasite. To invest this hypothesis we decided to modify the environment of the parasite of a way biotick and abiotique, when it develops within the definitive host or when it is for the contact of the intermediate host. Indeed, Schistosoma mansoni is an endoparasite thus every host, in whom he is going to remain, represents its direct environment. For it we used a drug anti-helminthe and an intermediate host allopatrique. The answer of the parasite to the various changes of environments was analyzed by the population (milked by life history) in the molecule (genome, épigénome, transcriptome). The new techniques of molecular biology and massive sequencing allowed us to realize global studies. During this thesis research, the various experimental evolutions led to two riddles: (1) " Fast Adaptation of Schistosoma mansoni to a drug anti-helminthes " and (2) " Fast Adaptation of Schistosoma mansoni to South America ". The results obtained for the latter brought the third riddle: (3) " Sexual Differentiation in the absence of gene W-spécifique in a system ZW "!La bilharziose est une maladie parasitaire humaine qui se trouve au second rang mondial, après la malaria, en termes de morbidité et de mortalité induites par le parasite. Plus de 200 millions de personnes sont infestées dans 74 pays et plus de 200 000 personnes décèdent par an (Chitsulo et al. 2004; Gryseels et al. 2006). Schistosoma mansoni, ici étudié, est responsable de la bilharziose intestinale. Ce parasite possède un cycle de vie complexe, passant obligatoirement à travers deux hôtes : un hôte intermédiaire mollusque d'eau douce et un hôte définitif humain ou murin. Lors du cycle de développement, les différents stades sont exposés à divers environnements. Par exemple, les stades larvaires peuvent être confrontés à plusieurs hôtes intermédiaires (souche de mollusque) ou définitifs (humain ou murin). Mes travaux de thèse concernent l'influence de l'environnement sur l'épigénome de Schistosoma mansoni. L'information épigénétique est une source supplémentaire pour la création de variants phénotypiques, nous proposons que certains de ces variants puissent être hérités et sélectionnés, et ainsi conférer un avantage au parasite.Pour investir cette hypothèse nous avons décidé de modifier l'environnement du parasite de façon biotique et abiotique, lorsqu'il se développe au sein de l'hôte définitif ou lorsqu'il est au contact de l'hôte intermédiaire. En effet, Schistosoma mansoni est un endoparasite donc chaque hôte, dans lequel il va se maintenir, représente son environnement direct. Pour cela nous avons utilisé une drogue anti-helminthe et un hôte intermédiaire allopatrique. La réponse du parasite aux différents changements d'environnements a été analysée de la population (traits d'histoire de vie) à la molécule (génome, épigénome, transcriptome). Les nouvelles techniques de biologie moléculaire et de séquençage massif nous ont permis de réaliser des études globales. Lors de ces travaux de thèse, les différentes évolutions expérimentales ont mené à deux énigmes : (1) " Adaptation rapide de Schistosoma mansoni à une drogue anti-helminthes " et (2) " Adaptation rapide de Schistosoma mansoni à l'Amérique du Sud ". Les résultats obtenus pour cette dernière ont amené une troisième énigme : (3) "Différenciation sexuelle en l'absence de gène W-spécifique dans un système ZW"