A male-derived nonribosomal peptide pheromone controls female schistosome development.

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 ß-alanyl-tryptamine that is released by paired male worms. Furthermore, synthetic ß-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.

Metabolomics reveal alterations in arachidonic acid metabolism in Schistosoma mekongi after exposure to praziquantel.

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.

Some facts on south asian schistosomiasis and need for international collaboration.

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.

Isothermal microcalorimetry accurately detects bacteria, tumorous microtissues, and parasitic worms in a label-free well-plate assay.

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.

The chronic enteropathogenic disease schistosomiasis.

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.

Schistosomiasis control: praziquantel forever?

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.

Human 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.

Casos autoctones de esquistossomose mansonica em criancas de Recife, PE / Casos autoctonos de esquistosomiasis mansonica en ninos de Recife, PE, Brasil / Autochthonous cases of schistosomiasis in children in Recife, Northeastern Brazil

OBJETIVO : Investigar criadouros com moluscos hospedeiros e casos humanos autóctones para esquistossomose. MÉTODOS : Entre julho de 2010 e setembro de 2012 foram realizados: (1) levantamento malacológico para busca ativa de criadouros, coleta e identificação de caramujos Biomphalaria positivos para Schistosoma mansoni em Recife, PE; (2) inquérito de prevalência com 2.718 escolares, de sete a 14 anos, para diagnóstico de casos de esquistossomose; (3) exame clínico e ultrassonografia nos casos positivos para S. mansoni. Os casos foram investigados quanto à sua autoctonia e avaliados clinicamente. Os casos e criadouros foram georreferenciados e espacializados. RESULTADOS : Foram identificados 30 criadouros de B. straminea , quatro deles potenciais focos de transmissão, uma vez que os testes moleculares identificaram DNA de S. mansoni nos caramujos coletados. Foram diagnosticadas 14 crianças com esquistossomose; entre elas, cinco foram consideradas casos autóctones da doença. CONCLUSÕES : Ações emergenciais pela vigilância em saúde são necessárias para evitar que a esquistossomose se endemize em Recife, como acontece em localidades litorâneas do estado de Pernambuco. .

OBJETIVO Investigar criaderos con moluscos hospedadores y casos humanos autóctonos para esquistosomiasis. MÉTODOS Se ejecutaron: estudio malacológico para búsqueda activa de criaderos, colecta e identificación de caracoles Biomphalaria positivos para S. mansoni en Recife, PE, entre julio de 2010 y septiembre de 2012, pesquisa de prevalencia con 2.718 escolares, de siete a 14 años, para diagnóstico de casos de esquistosomiasis, examen clínico y de ultrason en los casos positivos para S. mansoni. Los casos fueron investigados con respecto a su autoctonía y evaluados clínicamente. Los casos y criaderos fueron geo-referenciados y espacializados. RESULTADOS Se identificaron 30 criaderos de B. straminea, cuatro de ellos potenciales focos de transmisión, luego que las pruebas moleculares identificaron DNA de S. mansoni en los caracoles colectados. Se diagnosticaron 14 niños con esquistosomiasis, entre ellas cinco fueron considerados casos autóctonos de la enfermedad. CONCLUSIONES Acciones de emergencia para vigilancia de salud son necesarias para evitar que la esquistosomiasis se vuelva endémica en Recife como sucede en localidades del litoral de Pernambuco. .

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. .

Schistosomiasis chemotherapy.

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.

Cerebral and spinal schistosomiasis.

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.

Targeting schistosome histone modifying enzymes for drug development.

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.

Protein kinases as potential targets for novel anti-schistosomal strategies.

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.

New insight into praziquantel against various developmental stages of schistosomes.

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.

Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective?

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.

Pulmonary vascular disease associated with schistosomiasis.

In this article we focus on the pathogenesis and clinical characteristics of schistosomiasis infection on the lung vasculature. Overall, the basic biology and understanding of Schistosoma immune responses and their effect on the cardiopulmonary system is limited in both animal and human models, which hinders clinical care and drug development. The inflammatory response to the eggs in the lung appears to contribute to the remodeling of the pulmonary vessels. Portal hypertension caused by parasitemia also appears to contribute to the development of pathophysiologic alterations of the pulmonary vascular bed. Antischistosomal therapy, praziquantel, used for pulmonary hypertension secondary to schistosomiasis usually has no effect, but it is given to prevent further progression of disease. Currently, there are no clinical trials for the treatment of pulmonary vascular disease secondary to schistosomiasis. Specialty drugs such as phosphodiesterase type 5 or tyrosine kinase inhibitors exhibit some interesting activity, yet are prohibitively expensive, lack safety and efficacy studies in schistosomiasis endemic populations, and tend to be limited by safety, efficacy, route of administration and compliance problems.

Characteristics of granuloma formation and liver fibrosis in murine schistosomiasis mekongi: a morphological comparison between Schistosoma mekongi and S. japonicum infection.

A histopathological study was performed to clarify the characteristics of granuloma formation and liver fibrosis in Schistosoma mekongi infection in comparison with S. japonicum infection. Mice were exposed to S. mekongi (Laotian strain) and S. japonicum (Japanese strain) cercariae, and were dissected at 6, 8, 12, 16, and 20 weeks post-exposure. In the liver, granulomas in S. mekongi infection were cellular, initially organized with foam cells, and continuously appeared in the intralobular area, while granulomas in S. japonicum infection were fibrous and did not continuously appear in the intralobular area. Portal fibrosis was not seen in S. mekongi infection, but was commonly seen in S. japonicum infection in the later weeks. Granulomas in the small intestine were seen mainly in the submucosa with foam cells in S. mekongi infection and without foam cells in S. japonicum infection. The lung granulomas contained mainly histiocytes in both S. mekongi and S. japonicum infection. The absence of portal fibrosis in S. mekongi infection allows schistosome eggs to infiltrate into the intralobular area continuously, which can be what lies behind the ultrasonographic differences; the echogenic network pattern as was seen in S. japonicum infection, has not been noted in S. mekongi infection.