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Schistosomes cause morbidity and death throughout the developing world due to the massive numbers of eggs female worms deposit into the blood of their host. Studies dating back to the 1920s show that female schistosomes rely on constant physical contact with a male worm both to become and remain sexually mature; however, the molecular details governing this process remain elusive. Here, we uncover a nonribosomal peptide synthetase that is induced in male worms upon pairing with a female and find that it is essential for the ability of male worms to stimulate female development. We demonstrate that this enzyme generates β-alanyl-tryptamine that is released by paired male worms. Furthermore, synthetic β-alanyl-tryptamine can replace male worms to stimulate female sexual development and egg laying. These data reveal that peptide-based pheromone signaling controls female schistosome sexual maturation, suggesting avenues for therapeutic intervention and uncovering a role for nonribosomal peptides as metazoan signaling molecules., Competing Interests: Declaration of interests R.J.D. is on the SABs for Agios Pharmaceuticals, Vida Ventures, and Nirogyone Therapeutics and is a founder/advisor for Atavistik Biosciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Schistosomes cause schistosomiasis, the world's second most important parasitic disease after malaria in terms of public health and social-economic impacts. A peculiar feature of these dioecious parasites is their ability to produce viable and fertile hybrid offspring. Originally only present in the tropics, schistosomiasis is now also endemic in southern Europe. Based on the analysis of two genetic markers the European schistosomes had previously been identified as hybrids between the livestock- and the human-infective species Schistosoma bovis and Schistosoma haematobium, respectively. Here, using PacBio long-read sequencing technology we performed genome assembly improvement and annotation of S. bovis, one of the parental species for which no satisfactory genome assembly was available. We then describe the whole genome introgression levels of the hybrid schistosomes, their morphometric parameters (eggs and adult worms) and their compatibility with two European snail strains used as vectors (Bulinus truncatus and Planorbarius metidjensis). Schistosome-snail compatibility is a key parameter for the parasites life cycle progression, and thus the capability of the parasite to establish in a given area. Our results show that this Schistosoma hybrid is strongly introgressed genetically, composed of 77% S. haematobium and 23% S. bovis origin. This genomic admixture suggests an ancient hybridization event and subsequent backcrosses with the human-specific species, S. haematobium, before its introduction in Corsica. We also show that egg morphology (commonly used as a species diagnostic) does not allow for accurate hybrid identification while genetic tests do., Competing Interests: The authors have declared that no competing interests exist.

Background: Mekong schistosomiasis is a parasitic disease caused by the blood-dwelling fluke Schistosoma mekongi. This disease contributes to human morbidity and mortality in the Mekong region, posing a public health threat to people in the area. Currently, praziquantel (PZQ) is the drug of choice for the treatment of Mekong schistosomiasis. However, the molecular mechanisms of PZQ action remain unclear, and Schistosoma PZQ resistance has been reported occasionally. Through this research, we aimed to use a metabolomic approach to identify the potentially altered metabolic pathways in S. mekongi associated with PZQ treatment., Methodology/principal Findings: Adult stage S. mekongi were treated with 0, 20, 40, or 100 μg/mL PZQ in vitro. After an hour of exposure to PZQ, schistosome metabolites were extracted and studied with mass spectrometry. The metabolomic data for the treatment groups were analyzed with the XCMS online platform and compared with data for the no treatment group. After low, medium (IC50), and high doses of PZQ, we found changes in 1,007 metabolites, of which phosphatidylserine and anandamide were the major differential metabolites by multivariate and pairwise analysis. In the pathway analysis, arachidonic acid metabolism was found to be altered following PZQ treatment, indicating that this pathway may be affected by the drug and potentially considered as a novel target for anti-schistosomiasis drug development., Conclusions/significance: Our findings suggest that arachidonic acid metabolism is a possible target in the parasiticidal effects of PZQ against S. mekongi. Identifying potential targets of the effective drug PZQ provides an interesting viewpoint for the discovery and development of new agents that could enhance the prevention and treatment of schistosomiasis., Competing Interests: The authors have declared that no competing interests exist.

Schistosoma mekongi is found in the lower Mekong river region and causes schistosomiasis. Low sensitivity of diagnosis and development of drug resistance are problems to eliminate this disease. To develop novel therapies and diagnostics for S. mekongi , the basic molecular biology of this pathogen needs to be explored. Bioactive peptides have been reported in several worms and play important roles in biological functions. Limited information is available on the S. mekongi peptidome. Therefore, this study aimed to identify S. mekongi peptides using in silico transcriptome mining and mass spectrometry approaches. Schistosoma peptide components were identified in adult worms, eggs, and infected mouse sera. Thirteen neuropeptide families were identified using in silico predictions from in-house transcriptomic databases of adult S. mekongi worms. Using mass spectrometry approaches, 118 peptides (from 54 precursor proteins) and 194 peptides (from 86 precursor proteins) were identified from adult worms and eggs, respectively. Importantly, eight unique peptides of the S. mekongi ubiquitin thioesterase, trabid, were identified in infected mouse sera 14, 28, and 56 days after infection. This protein may be a potential target for diagnosis of schistosomiasis. The S. mekongi peptide profiles determined in this study could be used for further drug and diagnostic development.

Human schistosomes combat the unique immune systems of two vastly different hosts during their indirect life cycles. In gastropod molluscs, they face a potent innate immune response composed of variable immune recognition molecules and highly phagocytic hemocytes. In humans, a wide variety of innate and adaptive immune processes exist in proximity to these parasites throughout their lifespan. To survive and thrive as the second most common parasitic disease in humans, schistosomes have evolved many techniques to avoid and combat these targeted host responses. Among these techniques are molecular mimicry of host antigens, the utilization of an immune resistant outer tegument, the secretion of several potent proteases, and targeted release of specific immunomodulatory factors affecting immune cell functions. This review seeks to describe these key immune evasion mechanisms, among others, which schistosomes use to survive in both of their hosts. After diving into foundational observational studies of the processes mediating the establishment of schistosome infections, more recent transcriptomic and proteomic studies revealing crucial components of the host/parasite molecular interface are discussed. In order to combat this debilitating and lethal disease, a comprehensive understanding of schistosome immune evasion strategies is necessary for the development of novel therapeutics and treatment plans, necessitating the discussion of the numerous ways in which these parasitic flatworms overcome the immune responses of both hosts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hambrook and Hanington.)

Background: Avian schistosomes, the causative agents of human cercarial dermatitis (or swimmer's itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity., Methods: Inducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected by T. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluated in vivo. The vulnerability of T. regenti schistosomula to NO and peroxynitrite was assessed in vitro by viability assays and electron microscopy. Additionally, the effect of NO on the activity of T. regenti peptidases was tested using a fluorogenic substrate., Results: iNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord. In vitro, NO did not impair the parasites, but inhibited the activity of T. regenti cathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viability in vitro, but rather did not participate in parasite clearance in vivo., Conclusions: Reactive nitrogen species, specifically NO, do not directly kill T. regenti in mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.

Schistosomiasis remains a parasitic infection which poses serious public health consequences around the world, particularly on the African continent where cases of introgression/hybridization between human and cattle schistosomiasis are being discovered on a more frequent basis in humans, specifically between Schistosoma haematobium and S. bovis. The aim of this paper is to analyze the occurrence of S. bovis in cattle and its relationship with S. haematobium in an area where cattle and humans share the same site in Benin (West Africa). We used the chronobiology of cercarial emergence as an ecological parameter and both molecular biology (COI mtDNA and ITS rDNA) of the larvae and morphology of the eggs as taxonomic parameters. The results showed a chronobiological polymorphism in the cercarial emergence rhythm. They showed for the first time the presence of S. bovis in Benin, the presence of introgressive hybridization between S. bovis and S. haematobium in domestic cattle, and the presence of atypical chronobiological patterns in schistosomes from cattle, with typical S. haematobium shedding pattern, double-peak patterns, and nocturnal patterns. Our results showed that the chronobiological life-history trait is useful for the detection of new hosts and also may reveal the possible presence of introgressive hybridization in schistosomes. Our results, for the first time, place cattle as reservoir host for S. haematobium and S. bovis x S. haematobium. The consequences of these results on the epidemiology of the disease, the transmission to humans, and the control of the disease are very important.

Despite the low level expression of some long noncoding RNAs (lncRNAs), the differential expression of specific lncRNAs plays important roles during the development of many organisms. Schistosomes, parasitic flatworms that are responsible for schistosomiasis, infects over 200 million people resulting in chronic disease and hundreds of thousands of deaths. Schistosomes have a complex life cycle that transitions between molluscan and mammalian hosts. In a molluscan snail host, the sporocyst stage develops over 5 weeks undergoing asexual reproduction to give rise to free-swimming and infectious cercariae that penetrate human skin and eventually mature into egg producing worms in mammals. The tight integration of the sporocyst to the snail host hepatopancreas hinders the -omics study in the molluscan stage, so the sporocyst transcriptome has only been examined for lncRNAs in immature in vitro samples. Here we analyzed the in vivo mature sporocyst transcriptome to identify 4,930 total lncRNAs between the molluscan and mammalian stages of the parasite. We further demonstrate that the lncRNAs are differentially expressed in a development-dependent manner. In addition, we constructed a co-expression correlation network between lncRNAs and protein-coding (PC) genes that was used to identify clusters of lncRNA transcripts with potential functional relevance. We also describe lncRNA-lncRNA and lncRNA-kinome correlations that identify lncRNAs with prospective roles in gene regulation. Finally, our results show clear differential expression patterns of lncRNAs in host-dependent development stages of S. mansoni and ascribe potential functional roles in development based on predicted intracellular interaction.

Many parasites migrate through different tissues during their life-cycle, possibly with the aim to enhance their fitness. This is true for species of three parasite genera of global importance, Ascaris, Schistosoma and Plasmodium, which cause significant global morbidity and mortality. Interestingly, these parasites all incorporate the liver in their life-cycle. The liver has a special immune status being able to preferentially induce tolerance over immunity. This function may be exploited by parasites to evade host immunity, with Plasmodium spp. in particular using this organ for its multiplication. However, hepatic larval attrition occurs in both ascariasis and schistosomiasis. A better understanding of the molecular mechanisms involved in hepatic infection could be useful in developing novel vaccines and therapies for these parasites.

While disease and outbreaks are mainly clonal for bacteria and other asexually reproducing organisms, sexual reproduction in schistosomes and other helminths usually results in unique individuals. For sexually reproducing organisms, the traits conserved in clones will instead be conserved in the group of organisms that tends to breed together, the population. While the same tools are applied to characterize DNA, how results are interpreted can be quite different at times (see another article in this collection, http://www.asmscience.org/content/journal/microbiolspec/10.1128/microbiolspec.AME-0002-2018). It is difficult to know what the real effect any control program has on the parasite population without assessing the health of this population, how they respond to the control measure, and how they recover, if they do. This review, part of the Microbiology Spectrum Curated Collection: Advances in Molecular Epidemiology of Infectious Diseases, concentrates on one approach using pooled samples to study schistosome populations and shows how this and other approaches have contributed to our understanding of this parasite family's biology and epidemiology. *This article is part of a curated collection.

Chemotherapy based on repeated doses of praziquantel remains the most effective control strategy against schistosomiasis, a neglected tropical disease caused by platyhelminths of the genus Schistosoma spp. Its long-term use, however, raises serious concerns about drug resistance against praziquantel. Therefore, it is generally acknowledged that alternative treatment options are urgently needed. This Review summarizes data on relinquished drugs as well as recent advances in the area of antischistosomal compounds from a medicinal chemistry point of view. Furthermore, insights into the structure-activity relationships of each class of compounds are presented including in vitro and in vivo data, if available. Although many compounds have demonstrated good antischistosomal activity in vitro, they offer little promise to replace praziquantel. Nevertheless, the race to develop novel antischistosomal agents is ongoing., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Schistosomiasis caused by parasitic flatworms of blood flukes, remains a major public health concern in China. The significant progress in controlling schistosomiasis in China over the past decades has resulted in the remarkable reduction in the prevalence and intensity of Schistosoma japonicum infection to an extremely low level. Therefore, the elimination of schistosomiasis has been promoted by the Chinese national government. Hubei Province is the major endemic area, that is, along the middle and low reaches of the Yangtze River in the lake and marshland regions of southern China. Eliminating the transmission of schistosomiasis in Hubei Province is challenging. The current issue is to determine the distributions and clusters of schistosomiasis transmission. In this study, we assessed the spatial distribution of schistosomiasis and the risk at the county level in Hubei Province from 2011 to 2015 to provide guidance on the elimination of schistosomiasis transmission in lake and marshland regions. Spatial database of human S.japonicum infection from 2011 to 2015 at the county level in the study area was built based on the annual schistosomias is surveillance data. Moran's I, the global spatial autocorrelation statistics, was utilized to describe the spatial autocorrelation of human S. japonicum infection. In addition, purely spatial scan statistics combined with space-time scan statistics were used to determine the epidemic clusters. Infection rates of S. japonicum decreased in each endemic county in Hubei from 2011 to 2015. Human S. japonicum infection rate showed statistical significance by global autocorrelation analysis during the study period (Moran's I > 0, P < 0.01). This result suggested that there were spatial clusters present in the distribution of S. japonicum infection for the five years. Purely spatial analysis of human S. japonicum infection showed one most likely cluster and one secondary cluster from 2011 to 2015, which covered four and one counties, respectively. Spatiotemporal clustering analysis determined one most likely cluster and one secondary cluster both in 2011-2012, which appeared in 4 and 5 counties, respectively. However, the number of clustering foci decreased with time, and no cluster was detected after 2013.The clustering foci were both located at the Jianghan Plain, along the middle reaches of the Yangtze River and its connecting branch Hanbei River. Spatial distribution of human S. japonicum infections did not change temporally at the county level in Hubei Province. A declining trend in spatiotemporal clustering was observed between 2011 and 2015. However, effective control strategies and integrated prevention should be continuously performed, especially at the Jianghan Plain area along the Yangtze and Hanbei River Basin. Multivariate statistical analysis was carried out to investigate the risk of missing examinations, missing treatment, and unstandardized treatment events. The results showed that age, education level and Sanitary latrines are risk factors for missing examinations (b > 0, OR >1), and treatment times in past and feeding cattle in village group are protective factors (b < 0, OR <1). We also found that age and education level are risk factors for missing treatment (b > 0, OR >1). Study of the risk for un-standardized treatment revealed that occupation is risk factors (b > 0, OR >1), though, education level is protective factors (b < 0, OR <1). Therefore, precise prevention and control should be mainly targeted at these special populations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this review, we are discussing South Asian schistosomiasis; more specifically species which are responsible for schistosomiasis in India or South Asia -Schistosoma indicum, S. spindale, S. nasale, S. incognitum, S. gimvicum (S.haematobium), Bivitellobilharzia nairi, Orientobilharzia bomfordi, O. dattai, O. turkestanicum and O.harinasutai, their survival strategies such as mild pathology to the host, producing low egg number and utilizing fresh water snails (Indoplanorbis exustus and Lymnaea luteola) in stagnant water bodies like ponds, lakes, ditches, low laying areas, marshy lands and rice fields. Presently, correct identification of blood fluke species, their immature stages, male schistosomes and their intermediate host details like strain variations, susceptibilities, ecologies are not well studied. Species like B. nairi, O. bomfordi, O. harinasutai (Lymnaea rubiginosa intermediate host for O.harinasutai in Thailand) are also not well studied. Moreover, snail species like Oncomalania spp are not from South Asia, but species of Tricula or Neotricula are reported from this geography, which gives indications of S. mekongi like blood fluke presence in the area. Although in humans, cercarial dermatitis is rampant in rural population with occasional reporting of schistosome eggs in stools, human schistosomiasis is considered absent from this region, despite finding a foci (now dead) of urinary schistosomiasis in Gimvi village of Ratnagiri district, Maharashtra, India. There is great difficulty in diagnosing the infection in man and animals due to low egg production, hence development of a single step antigen detection test is the need of the hour. Interestingly, lethal effect of praziquantel was seen against S.haematobium and S.mansoni. However, this drug failed to cause significant reduction of S. incognitum and S. spindale experimentally suggesting some differences in the biology of two groups of the schistosomes. Triclabendazole showed adulticidal effect at a dose rate of 20 mg/kg body against female schistosome worms, but at lower dose (10 mg/kg body wt) of the drug, a dose that is used in treating bovine fascioliasis, it is providing chances of drug resistance of the persisting schistosomes against triclabendazole. Though the South Asian institutes have all the facilities to tackle issues related to existing schistosomes, it is recommended to develop an international collaboration by establishing an international centre on schistosomiasis in India., (Copyright © 2017. Published by Elsevier B.V.)

Understanding schistosome biology is still a challenging mission. The reproductive biology of this parasitic trematode is closely associated with the pathologic consequences of schistosomiasis, the devastating infectious disease caused by members of the family Schistosomatidae worldwide. Recent studies of signaling mechanisms confirmed the prominent roles of protein kinases (PKs) in directing schistosome biology, and first evidence was obtained for an additional contribution of kinases with substrates different from proteins (non-PKs). This review provides an overview of the Schistosoma mansoni kinome in the context of male-female interaction and summarizes recent studies of kinases controlling development and differentiation. Due to their importance for schistosome biology, kinases represent Achilles' heels and are therefore of high value also for translational research., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Schistosomes are trematode parasites of global importance, causing infections in millions of people, livestock, and wildlife. Most studies on schistosomiasis, involve human subjects; as such, there is a paucity of longitudinal studies investigating parasite dynamics in the absence of intervention. As a consequence, despite decades of research on schistosomiasis, our understanding of its ecology in natural host populations is centered around how environmental exposure and acquired immunity influence acquisition of parasites, while very little is known about the influence of host physiology, coinfection and clearance in the absence of drug treatment. We used a 4-year study in free-ranging African buffalo to investigate natural schistosome dynamics. We asked (i) what are the spatial and temporal patterns of schistosome infections; (ii) how do parasite burdens vary over time within individual hosts; and (iii) what host factors (immunological, physiological, co-infection) and environmental factors (season, location) explain patterns of schistosome acquisition and loss in buffalo? Schistosome infections were common among buffalo. Microgeographic structure explained some variation in parasite burdens among hosts, indicating transmission hotspots. Overall, parasite burdens ratcheted up over time; however, gains in schistosome abundance in the dry season were partially offset by losses in the wet season, with some hosts demonstrating complete clearance of infection. Variation among buffalo in schistosome loss was associated with immunologic and nutritional factors, as well as co-infection by the gastrointestinal helminth Cooperia fuelleborni. Our results demonstrate that schistosome infections are surprisingly dynamic in a free-living mammalian host population, and point to a role for host factors in driving variation in parasite clearance, but not parasite acquisition which is driven by seasonal changes and spatial habitat utilization. Our study illustrates the power of longitudinal studies for discovering mechanisms underlying parasite dynamics in individual animals and populations.

Background: Schistosomiasis caused by blood-dwelling flukes, namely Schistosoma mansoni and Schistosoma haematobium is a severe debilitating disease, widespread in sub-Saharan Africa, the Middle East, and South America. Developing and adult worms are unscathed by the surrounding immune effectors and antibodies because the parasite is protected by a double lipid bilayer armor which allows access of nutrients, while binding of specific antibodies is denied., Scope of Review: Fluorescence recovery after bleaching, extraction of surface membrane cholesterol by methyl-β-cyclodextrin, inhibition and activation of sphingomyelin biosynthesis and hydrolysis, and elastic incoherent and quasi-elastic neutron scattering approaches have helped to clarify the basic mechanism of this immune evasion, and showed that sphingomyelin (SM) molecules in the worm apical lipid bilayer form with surrounding water molecules a tight hydrogen bond barrier. Viability of the parasite and permeability of the outer shield are controlled by equilibrium between SM biosynthesis and activity of a tegument-associated neutral sphingomyelinase (nSMase)., Major Conclusions: Excessive nSMase activation by polyunsaturated fatty acids (PUFA), such as arachidonic acid (ARA) leads to disruption of the SM molecules and associated hydrogen bond network, with subsequent access of host antibodies and immune effectors to the outer membrane and eventual parasite death., General Significance: ARA was predicted and shown to be a potent schistosomicide in vitro and in vivo in experimental animals and in children. Additionally, it was advocated that schistosomiasis vaccine candidates should be selected uniquely among excretory-secretory products of developing worms, as contrary to cytosolic and surface membrane antigens, they are able to activate the effector functions of the host antibodies and toxic molecules. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo"., (Copyright © 2016 Elsevier B.V. All rights reserved.)

For scientists working on gonochoric organisms, determining sex can be crucial for many biological questions and experimental studies, such as crossbreeding, but it can also be a challenging task, particularly when no sexual dimorphism is visible or cannot be directly observed. In metazoan parasites of the genus Schistosoma responsible for schistosomiasis, sex is genetically determined in the zygote with a female heterogametic ZW/ZZ system. Adult flukes have a pronounced sexual dimorphism, whereas the sexes of the larval stages are morphologically indistinguishable but can be distinguished uniquely by using molecular methods. Therefore, reliable methods are needed to identify the sex of larvae individuals. Here, we present an endpoint PCR-based assay using female-specific sequences identified using a genome-wide comparative analysis between males and females. This work allowed us to identify sex-markers for Schistosoma haematobium and Schistosoma bovis but also the hybrid between both species that has recently emerged in Corsica (France). Five molecular sex-markers were identified and are female-specific in S. haematobium and the hybrid parasite, whereas three of them are also female-specific in S. bovis. These molecular markers will be useful to conduct studies, such as experimental crosses on these disease-causing blood flukes, which are still largely neglected but no longer restricted to tropical areas., Competing Interests: The authors have declared that no competing interests exist.

Schistosomes are metazoan parasites and can cause schistosomiasis. Epigenetic modifications include DNA methylation, histone modifications and non-coding RNAs. Some enzymes involved in epigenetic modification and microRNA processes have been developed as drugs to treat the disease. Compared with humans and vertebrates, an in-depth understanding of epigenetic modifications in schistosomes is starting to be realized. DNA methylation, histone modifications and non-coding RNAs play important roles in the development and reproduction of schistosomes and in interactions between the host and schistosomes. Therefore, exploring and investigating the epigenetic modifications in schistosomes will facilitate drug development and therapy for schistosomiasis. Here, we review the role of epigenetic modifications in the development, growth and reproduction of schistosomes, and the interactions between the host and schistosome. We further discuss potential epigenetic targets for drug discovery for the treatment of schistosomiasis.

Purpose of Review: Schistosomiasis is one of the most prevalent parasitic diseases in the world, being present in more than 70 countries. Pulmonary hypertension is one of the several chronic complications of schistosomiasis; particularly in developing countries, schistosomiasis-associated pulmonary arterial hypertension might represent one of the most prevalent causes of pulmonary arterial hypertension., Recent Findings: New epidemiological data reinforce the importance of schistosomiasis in the context of pulmonary hypertension; furthermore, the inflammatory components of the pathophysiology of pulmonary hypertension associated with schistosomiasis have been recently explored, opening the perspective of new targets to be explored. Clinical and hemodynamic features of this particular complication of schistosomiasis, and the role of targeted therapies in this setting, have been better described in recent years., Summary: The importance of schistosomiasis-associated pulmonary hypertension is now recognized with better knowledge about its pathophysiology and management. Nevertheless, there is a need for better understanding the predisposal factors (genetic, environmental and so on) for the development of pulmonary hypertension in schistosomiasis as a way to prevent it from occurring. Furthermore, better control programs to decrease disease transmission are still missing, ensuring that we will have to face this devastating complication of schistosomiasis for a long future.

Background: Schistosoma parasites sustain a complex transmission process that cycles between a definitive human host, two free-swimming larval stages, and an intermediate snail host. Multiple factors modify their transmission and affect their control, including heterogeneity in host populations and environment, the aggregated distribution of human worm burdens, and features of parasite reproduction and host snail biology. Because these factors serve to enhance local transmission, their inclusion is important in attempting accurate quantitative prediction of the outcomes of schistosomiasis control programs. However, their inclusion raises many mathematical and computational challenges. To address these, we have recently developed a tractable stratified worm burden (SWB) model that occupies an intermediate place between simpler deterministic mean worm burden models and the very computationally-intensive, autonomous agent models., Methods: To refine the accuracy of model predictions, we modified an earlier version of the SWB by incorporating factors representing essential in-host biology (parasite mating, aggregation, density-dependent fecundity, and random egg-release) into demographically structured host communities. We also revised the snail component of the transmission model to reflect a saturable form of human-to-snail transmission. The new model allowed us to realistically simulate overdispersed egg-test results observed in individual-level field data. We further developed a Bayesian-type calibration methodology that accounted for model and data uncertainties., Results: The new model methodology was applied to multi-year, individual-level field data on S. haematobium infections in coastal Kenya. We successfully derived age-specific estimates of worm burden distributions and worm fecundity and crowding functions for children and adults. Estimates from the new SWB model were compared with those from the older, simpler SWB with some substantial differences noted. We validated our new SWB estimates in prediction of drug treatment-based control outcomes for a typical Kenyan community., Conclusions: The new version of the SWB model provides a better tool to predict the outcomes of ongoing schistosomiasis control programs. It reflects parasite features that augment and perpetuate transmission, while it also readily incorporates differences in diagnostic testing and human sub-population differences in treatment coverage. Once extended to other Schistosoma species and transmission environments, it will provide a useful and efficient tool for planning control and elimination strategies.

Objective: to characterize printed educational materials about schistosomiasis produced at federal, state and municipal levels in Brazil., Methods: the educational materials were characterized considering the following categories: 'format', 'parasite and intermediate host', 'definitive host (ill)' and 'disease'., Results: 60 materials were assessed, three had no information about risk activities and 41 indicated more than one popular name for the disease, thus allowing greater reach among the target audience in diverse endemic areas; the biological cycle was missing or incorrect in 53 materials; the intermediate host (snail) was incorrectly illustrated, with use of stereotyped images in 39 and no image in one material; diagnosis was mentioned in 36 materials., Conclusion: the printed educational materials assessed had incorrect content which may compromise health education efforts; little attention was paid to schistosomiasis diagnosis.

Summary: Neglected tropical diseases (NTDs) caused by helminths constitute some of the most common infections of the world's poorest people. The etiological agents are complex and recalcitrant to standard techniques of molecular biology. Drug screening against helminths has often been phenotypic and typically involves manual description of drug effect and efficacy. A key challenge is to develop automated, quantitative approaches to drug screening against helminth diseases. The quantal dose-response calculator (QDREC) constitutes a significant step in this direction. It can be used to automatically determine quantitative dose-response characteristics and half-maximal effective concentration (EC50) values using image-based readouts from phenotypic screens, thereby allowing rigorous comparisons of the efficacies of drug compounds. QDREC has been developed and validated in the context of drug screening for schistosomiasis, one of the most important NTDs. However, it is equally applicable to general phenotypic screening involving helminths and other complex parasites., Availability and Implementation: QDREC is publically available at: http://haddock4.sfsu.edu/qdrec2/. Source code and datasets are at: http://tintin.sfsu.edu/projects/phenotypicAssays.html., Contact: rahul@sfsu.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Isothermal microcalorimetry is a label-free assay that allows monitoring of enzymatic and metabolic activities. The technique has strengths, but most instruments have a low throughput, which has limited their use for bioassays. Here, an isothermal microcalorimeter, equipped with a vessel holder similar to a 48-well plate, was used. The increased throughput of this microcalorimeter makes it valuable for biomedical and pharmaceutical applications. Our results show that the sensitivity of the instrument allows the detection of 3 × 10(4) bacteria per vial. Growth of P. mirabilis in Luria Broth medium was detected between 2 and 9 h with decreasing inoculum. The culture released 2.1J with a maximum thermal power of 76 μW. The growth rate calculated using calorimetric and spectrophotometric data were 0.60 and 0.57 h(-1) , respectively. Additional insight on protease activities of P. mirabilis matching the last peak in heat production could be gathered as well. Growth of tumor microtissues releasing a maximum thermal power of 2.1 μW was also monitored and corresponds to a diameter increase of the microtissues from ca. 100 to 428 μm. This opens new research avenues in cancer research, diagnostics, and development of new antitumor drugs. For parasitic worms, the technique allows assessment of parasite survival using motor and metabolic activities even with a single worm., (© 2015 The Authors. Biotechnology Journal published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Objective: To evaluate the efficacy of routinely used pattern for schistosomiasis diagnosis in lake and marshland regions., Methods: A historically heavy endemic village of schistosomiasis named Jinggan Village from Jiangling County was selected for field survey. The residents aged 6-65 years were screened by indirect hemagglutination assay (IHA) and dipstick dye immunoassay (DDIA) in parallel. The serological positives were examined by Kato-Katz technique and miracidium hatching technique to determine the infection of schistosome. The consistency of the two serological methods was evaluated. In addition, the schistosome infection rates were estimated accordingto the 3 detection patterns namely IHA, DDIA, IHA+DDIA combined with the etiologic examination., Results: A total of 530 individuals were examined by the serological tests. The positive rate of DDIA was 46.98% (249/530), significantly higher than that of IHA (28.49%, 151/530) (χ2 = 59.55, P < 0.01). Totally 279 individuals were serological positives determined by IHA or DDIA, while 252 of them were detected by stool examination, and 22 cases were determined as parasitological positives, while 7 and 3 cases were diagnosed as antibody negatives by IHA and DDIA, respectively. The estimated infection rates determined by IHA, DDIA, IHA plus DDIA combined with stool examination were 3.14%, 3.97%, 4.60%, respectively., Conclusions: Under the condition of endemic situation becoming more and more waning, the current routinely used pattern for schistosomiasis detection may lead to missed diagnosis. So, more sensitive and effective diagnostic tools or appropriate detection patterns need to be explored.

Schistosomiasis is a chronic enteropathogenic disease caused by blood flukes of the genus Schistosoma. The disease afflicts approximately 240 million individuals globally, causing approximately 70 million disability-adjusted life years lost. Chronic infections with morbidity and mortality occur as a result of granuloma formation in the intestine, liver, or in the case of Schistosoma haematobium, the bladder. Various methods are utilized to diagnose and evaluate liver fibrosis due to schistosomiasis. Liver biopsy is still considered the gold standard, but it is invasive. Diagnostic imaging has proven to be an invaluable method in assessing hepatic morbidity in the hospital setting, but has practical limitations in the field. The potential of non-invasive biological markers, serum antibodies, cytokines, and circulating host microRNAs to diagnose hepatic fibrosis is presently undergoing evaluation. This review provides an update on the recent advances made with respect to gastrointestinal disease associated with chronic schistosomiasis.

Human schistosomiasis--or bilharzia--is a parasitic disease caused by trematode flukes of the genus Schistosoma. By conservative estimates, at least 230 million people worldwide are infected with Schistosoma spp. Adult schistosome worms colonise human blood vessels for years, successfully evading the immune system while excreting hundreds to thousands of eggs daily, which must either leave the body in excreta or become trapped in nearby tissues. Trapped eggs induce a distinct immune-mediated granulomatous response that causes local and systemic pathological effects ranging from anaemia, growth stunting, impaired cognition, and decreased physical fitness, to organ-specific effects such as severe hepatosplenism, periportal fibrosis with portal hypertension, and urogenital inflammation and scarring. At present, preventive public health measures in endemic regions consist of treatment once every 1 or 2 years with the isoquinolinone drug, praziquantel, to suppress morbidity. In some locations, elimination of transmission is now the goal; however, more sensitive diagnostics are needed in both the field and clinics, and integrated environmental and health-care management will be needed to ensure elimination., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Since no vaccine exists against schistosomiasis and the molluscs acting as intermediate hosts are not easy to attack, chemotherapy is the main approach for schistosomiasis control. Praziquantel is currently the only available antischistosomal drug and it is distributed mainly through mass administration programs to millions of people every year. A number of positive features make praziquantel an excellent drug, especially with regard to safety, efficacy, cost and ease of distribution. A major flaw is its lack of efficacy against the immature stages of the parasite. In view of its massive and repeated use on large numbers of individuals, the development of drug resistance is a much feared possibility. The mechanism of action of praziquantel is still unclear, a fact that does not favor the development of derivatives or alternatives. A large number of compounds have been tested as potential antischistosomal agents. Some of them are promising, but none so far represents a suitable substitute or adjunct to praziquantel. The research of new antischistosomal compounds is an imperative and urgent matter., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Schistosomiasis is a parasitic infection that causes significant morbidity and mortality, especially in pregnant women originating from developing countries. Prompt diagnosis and treatment can improve pregnancy and infant outcomes. Currently, there are no formal guidelines for treatment in this population, which makes schistosomiasis in pregnancy a challenge to treat.

Objective: Investigate breeding sites with host snails and autochthonous human cases of schistosomiasis., Methods: Between July 2010 and September 2012 were performed: (1) malacological survey searching for breeding sites, collection and identification of Biomphalaria snails positive for Schistosoma mansoni in Recife, PE, Northeastern Brazil; (2) prevalence survey in 2,718 schoolchildren aged from seven to 14 years old to identify cases of schistosomiasis, clinical examination and ultrasound in positive cases of S. mansoni. The autochthony of the cases was investigated and the case were clinically evaluated. The cases and breeding sites were georeferenced and spatially described., Results: The results identified 30 breeding with B. straminea, four of which were potential foci of transmission, as molecular testing identified snails with S. mansoni DNA. There were 14 children diagnosed with schistosomiasis, of which five were considered to be autochthonous cases of the disease., Conclusions: Urgent measures are required in order to avoid schistosomiasis becoming endemic to Recife, as has happened in other coastal areas of the state of Pernambuco.

After malaria, schistosomiasis (or bilharzia) is the second most prevalent disease in Africa, and is occurring in over 70 countries in tropical and subtropical regions. It is estimated that 600 million people are at risk of infection, 200 million people are infected, and at least 200,000 deaths per year are associated with the disease. All schistosome species are transmitted through contact with fresh water that is infested with free-swimming forms of the parasite, which is known as cercariae and produced by snails. When located in the blood vessels of the host, larval and adult schistosomes digest red cells to acquire amino acids for growth and development. Vaccine candidates have been unsuccessful up to now. Against such devastating parasitic disease, the antischistosomal arsenal is currently limited to a single drug, praziquantel, which has been used for more than 35 years. Because the question of the reduction of the activity of praziquantel was raised recently, it is thus urgent to create new and safe antischistosomal drugs that should be combined with praziquantel to develop efficient bitherapies., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cerebral schistosomiasis and spinal schistosomiasis are severe underrecognized complications of Schistosoma sp. infection, and can occur at any time during the parasitic infection. Neuroschistosomiasis has been increasingly reported not only in endemic areas but also in Western countries owing to immigration and international travel. Immunogenic interaction between schistosome egg deposition and the delayed hypersensitivity reaction of the host are the main neuropathogenic mechanisms involved. Eggs induce a periovular granulomatous reaction in the tissues. In some cases, schistosome adult worms may aberrantly migrate to the central nervous system via the vertebral venous plexus and place the ova at an ectopic site. Headache and seizures are common in cerebral schistosomiasis, and intracranial hypertension and hydrocephalus may occur in tumour-like and cerebellar schistosomiasis. Spinal schistosomiasis may manifest itself as acute myelitis and/or myeloradiculopathy. Recognition of neuroschistosomiasis is important so that early treatment with praziquantel and steroids can be started in an attempt to prevent severe disability.

The specific molecular targets of schistosomula have been investigated for being new vaccine candidates. The mechanism of the growth and development of the skin-stage, lung-stage and hepatic schistosomula may be related to the immune regulation, signal transduction, sex-differentiation and apoptosis. Actin et al are important molecules which related to the growth and development of schistosomula.

This review of schistosome cell biology has a dual purpose; its intent is to alert two separate research communities to the activities of the other. Schistosomes are by far and away the best-characterised platyhelminths, due to their medical and economic importance, but seem to be almost totally ignored by researchers on the free-living lower metazoans. Equally, in their enthusiasm for the parasitic way of life, schistosome researchers seldom pay attention to the work on free-living animals that could inform their molecular investigations. The publication of transcriptomes and/or genomes for Schistosoma mansoni and Schistosoma japonicum, the sponge Archimedon, the cnidarians Nematostella and Hydra and the planarian Schmidtea provide the raw material for comparisons. Apart from interrogation of the databases for molecular similarities, there have been differences in technical approach to these lower metazoans; widespread application of whole mount in situ hybridisation to Schmidtea contrasts with the application of targeted proteomics to schistosomes. Using schistosome cell biology as the template, the key topics of cell adhesion, development, signalling pathways, nerve and muscle, and epithelia, are reviewed, where possible interspersing comparisons with the sponge, cnidarian and planarian data. The biggest jump in the evolution of cellular capabilities appears to be in the transition from a diploblast to triploblast level of organisation associated with development of a mobile and plastic body form.

MicroRNAs (miRNAs) are small, endogenous non-coding RNA molecules that regulate gene expression post-transcriptionally by targeting the 3' untranslated region (3' UTR) of messenger RNAs. Since the discovery of the first miRNA in Caenorhabditis elegans, important regulatory roles for miRNAs in many key biological processes including development, cell proliferation, cell differentiation and apoptosis of many organisms have been described. Hundreds of miRNAs have been identified in various multicellular organisms and many are evolutionarily conserved. Schistosomes are multi-cellular eukaryotes with a complex life-cycle that require genes to be expressed and regulated precisely. Recently, miRNAs have been identified in two major schistosome species, Schistosoma japonicum and S. mansoni. These miRNAs are likely to play critical roles in schistosome development and gene regulation. Here, we review recent studies on schistosome miRNAs and discuss the potential roles of miRNAs in schistosome development and gene regulation. We also summarize the current status for targeting miRNAs and the potential of this approach for therapy against schistosomiasis.

The histone modifying enzymes (HME) represent particularly promising targets for the development of alternatives to praziquantel, the only currently available drug to combat schistosomiasis. The inhibition of these enzymes frequently arrests the cell cycle or induces apoptosis in cancer cells, but not in normal cells and numerous HME inhibitors are under investigation as potential anticancer agents. The recent resolution of the genome sequences of Schistosoma mansoni and Schistosoma japonicum has allowed us to identify all the schistosome genes encoding histone acetyltransferases, deacetylases, methyltransferases and demethylases. We have chosen a strategy using phylogenetic screening with inhibitors of HME classes, screening of individual HME targets by both high-throughput and reasoned (in silico docking using resolved crystal structures) approaches in a project funded by the European Community, named SEtTReND (Schistosome Epigenetics: Targets, Regulation, New Drugs). The initial focus is on the class I histone deacetylase (HDAC) 8 since the comparison of the catalytic site of the schistosome and human enzymes shows crucial differences, rendering possible the development of inhibitors specific for SmHDAC8. However, phenotypic screening shows that inhibitors of all HME classes tested were able to induce apoptosis and death in parasites in vitro, indicating that other enzymes may prove to be viable targets.

The role of redox enzymes in establishing a microenvironment for parasite development is well characterized. Mimicking human glucose-6-phosphate dehydrogenase and glutathione reductase (GR) deficiencies by redox-cycling compounds thus represents a challenge to the design of new preclinical antiparasitic drug candidates. Schistosomes and malarial parasites feed on hemoglobin. Heme, the toxic prosthetic group of the protein, is not digested and represents a challenge to the redox metabolism of the parasites. Here, we report on old and new redox-cycling compounds--whose antiparasitic activities are related to their interference with (met)hemoglobin degradation and hematin crystallization. Three key-assays allowed probing and differentiating the mechanisms of drug actions. Inhibition of β-hematin was first compared to the heme binding as a possible mode of action. All tested ligands interact with the hematin π-π dimer with K(D) similar to those measured for the major antiparasitic drugs. No correlation between a high affinity for hematin and the capacity to prevent β-hematin formation was however deduced. Inhibition of β-hematin formation is consequently not the result of a single process but results from redox processes following electron transfers from the drugs to iron(III)-containing targets. The third experiment highlighted that several redox-active compounds (in their reduced forms) are able to efficiently reduce methemoglobin to hemoglobin in a GR/NADPH-coupled assay. A correlation between methemoglobin reduction and inhibition of β-hematin was shown, demonstrating that both processes are closely related. The ability of our redox-cyclers to trigger methemoglobin reduction therefore constitutes a critical step to understand the mechanism of action of our drug candidates.

Schistosome parasites are the causative pathogens of schistosomiasis (bilharzia), a disease of worldwide significance. In terms of patient numbers, schistosomiasis ranks second to malaria as a parasitosis affecting more than 200 million people of the tropics and subtropics. Since the 1970s Praziquantel (PZQ) is the drug of choice and nearly exclusively used for treatment. However, drug resistance is an increasing threat, particularly with respect to large-scale PZQ administration programs. Last decade's research indicated that resistance against PZQ can be induced under laboratory conditions, and field studies provided first indications for the possibility of reduced PZQ efficacy. Furthermore, clear evidence for the molecular armamentarium of schistosomes with multidrug transporters was found, one of which was responding to PZQ challenge. Also the development of a vaccine still represents an elusive goal, although effort and time have been invested in this subject. In light of these facts it is commonly accepted that new drugs are urgently needed. Research on signal transduction processes in Schistosoma mansoni has provided an unexpected and novel perspective towards this end. Molecular, biochemical, and physiological studies elucidating principles of schistosome development have demonstrated the essential role of protein kinases (PKs). In humans, PKs are known to be involved in cancer development. Since a variety of approved anticancer drugs targeting PKs exist, first studies have been performed to investigate whether these drugs are able to also inhibit schistosome PKs. Indeed, promising results have been obtained indicating the potential of PKs as privileged targets for new concepts in fighting schistosomes.

With just one drug used for individual patient management and community-based morbidity control, the treatment, control, and eventual elimination of schistosomiasis is vulnerable should resistance to praziquantel emerge and spread. The discovery and development of novel chemical entities that exhibit antischistosomal properties, and the repurposing of existing drugs for schistosomiasis is thus of central importance as long as praziquantel remains effective. Here, we discuss the public health relevance of schistosomiasis, which is currently considered a neglected tropical disease. We recapitulate the past and current drug armamentarium against schistosomiasis, including shortcomings and a target product profile of an antischistosomal drug. The central piece of our review is the discovery of the antischistosomal properties of various antimalarial drugs, notably the artemisinins, synthetic trioxolanes, and mefloquine. We summarize findings from preclinical investigations and experiences made thus far from clinical studies. We conclude that a closer collaboration between the malaria and schistosomiasis communities might facilitate the discovery and development of novel antischistosomal drugs, and will foster monitoring and evaluation of the ancillary benefits of antimalarial prophylaxis and treatment against schistosomiasis.

Schistosomiasis caused by Schistosoma spp. is a serious public health concern, especially in sub-Saharan Africa. Praziquantel is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Antioxidants are appealing drug targets. In order to survive in their hosts, schistosomes are challenged by reactive oxygen species from intrinsic and extrinsic sources. Schistosome antioxidant enzymes have been identified as essential proteins and novel drug targets and inhibition of the antioxidant response can lead to parasite death. Because the organization of the redox network in schistosomes is significantly different from that in humans, new drugs are being developed targeting schistosome antioxidants. In this paper the redox biology of schistosomes is discussed and their potential use as drug targets is reviewed. It is hoped that compounds targeting parasite antioxidant responses will become clinically relevant drugs in the near future.

Praziquantel, due to high efficacy, excellent tolerability, few and transient side effects, simple administration, and competitive cost, is virtually the only drug of choice for treatment of human schistosomiasis. Treatment of schistosomiasis has shown great advances with the introduction of the drug into the therapeutic arsenal in areas that are endemic for the parasite. However, the drug presents various efficacies against different developmental stages of schistosomes, appearing an oddity intermitted mode. The present review article reviews the effects and mechanism of action of praziquantel against schistosomes briefly and suggests the research on this oddity phenomenon.

The need to discover new treatments for human schistosomiasis has been an important driver for molecular research on schistosomes, a major breakthrough being the publication of the Schistosoma mansoni and Schistosoma japonicum genomes in 2009. This 'Primer' considers recent advances in the understanding of schistosome biology by providing a snapshot of selected areas of contemporary functional schistosome research, including that on the genome, the tegument, cell signalling and developmental biology, offering biologists a valuable insight into the life of these fascinating parasites at the basic and molecular level.

Objective: To understand and evaluate the quality of feces examination for schistosomiasis in province-level laboratories of Zhejiang Province., Method: With the single-blind method, the stool samples were detected by the stool hatching method and sediment detection method., Results: In the 3 quality control assessments in 2006, 2008 and 2009, most laboratories finished the examinations on time. The accordance rates of detections were 88.9%, 100% and 93.9%, respectively., Conclusion: The province-level laboratories for schistosomiasis feces examination of Zhejiang Province is coming into standardization, and the techniques of schistosomiasis feces examination are optimized gradually.

The source of infection of schistosomiasis and snail situation in Hubei section of the Three Gorge Reservoir areas from 2007 to 2009 were investigated by combined epidemiological, immunological and field survey. The results showed that there were no local residents and livestock infected with shchistosome, and no Oncomelania snails were found, but 4 cases of imported patients with chronic schistosomiasis were checked out. It is suggested that the surveillance and intervention should be strengthened pointing to the risk of schistosomiasis transmission in the Three Gorge Reservoir areas, so as to prevent schistosomiasis being endemic in these areas.

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. Recent studies of signaling proteins in schistosomes uncovered a way of achieving this goal relatively quickly. It was shown that protein kinases (PKs) control important biological processes in schistosomes. Concurrently, the involvement of mutant forms of PKs was demonstrated in the etiology of cancer. Therefore, different anticancer drugs have been developed to inhibit deregulated PKs. These can also inhibit schistosome PKs, thus blocking parasite development. Recent studies characterizing schistosome PKs are summarized and we discuss the concept of PK inhibitors, including approved cancer drugs, as novel candidate anti-schistosome agents. This is also likely to be of significance for other worm infections., (Copyright © 2010 Elsevier Ltd. All rights reserved.)