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BACKGROUND: Schistosomiasis is a common cause of pulmonary hypertension (PH) worldwide. Type 2 inflammation contributes to the development of Schistosoma-induced PH. Specifically, interstitial macrophages (IMs) derived from monocytes play a pivotal role by producing thrombospondin-1 (TSP-1), which in turn activates TGF-β, thereby driving the pathology of PH. Resident and recruited IM subpopulations have recently been identified. We hypothesized that in Schistosoma-PH, one IM subpopulation expresses monocyte recruitment factors, whereas recruited monocytes become a separate IM subpopulation that expresses TSP-1. METHODS: Mice were intraperitoneally sensitized and then intravenously challenged with S. mansoni eggs. Flow cytometry on lungs and blood was performed on wildtype and reporter mice to identify IM subpopulations and protein expression. Single-cell RNA sequencing (scRNAseq) was performed on flow-sorted IMs from unexposed and at day 1, 3 and 7 following Schistosoma exposure to complement flow cytometry based IM characterization and identify gene expression. RESULTS: Flow cytometry and scRNAseq both identified 3 IM subpopulations, characterized by CCR2, MHCII, and FOLR2 expression. Following Schistosoma exposure, the CCR2+ IM subpopulation expanded, suggestive of circulating monocyte recruitment. Schistosoma exposure caused increased monocyte-recruitment ligand CCL2 expression in the resident FOLR2+ IM subpopulation. In contrast, the vascular pathology-driving protein TSP-1 was greatest in the CCR2+ IM subpopulation. CONCLUSION: Schistosoma-induced PH involves crosstalk between IM subpopulations, with increased expression of monocyte recruitment ligands by resident FOLR2+ IMs, and the recruitment of CCR2+ IMs which express TSP-1 that activates TGF-β and causes PH.

Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, Schistosoma mansoni. Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected SmBRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for SmBRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rational design of a quinoline-based ligand (15) with an ITC Kd = 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays.

Schistosomiasis is one of the most common causes of morbidity and mortality from parasitic diseases. Mass treatment has proven to be insufficient because of repeated infection after treatment and the appearance of strains resistant to drug therapy. Hence, immunization is a new approach to control the disease and limit the pathological consequences of schistosomiasis. To evaluate the prophylactic effect of Cercarial antigen (CAP) loaded on chitosan nanoparticles (CSNPs) as a potential vaccine against Schistosoma mansoni-infected mice. 130 mice divided into 2 groups were used: Group I: Control groups (50 mice) subdivided into subgroup Ia (10 mice): Non-infected mice (normal control), subgroup Ib (20 mice): Schistosoma infected mice (infected control) and subgroup Ic (20 mice): Non-infected mice receiving NPs only. Group II: Vaccinated group (80 mice) subdivided equally into subgroup IIa (CAP): Received cercarial antigen and subgroup IIb (CAP + CSNP): Received cercarial antigen loaded on chitosan NPs then both vaccinated groups were infected with S. mansoni 3 weeks following the initial vaccination dose. CAP + CSNP and CAP groups showed significant reduction in adult worms count, hepatic egg count, hepatic granulomas number and size in comparison to the infected control group. Elevation of serum IgG and IgM levels, CD4+ and CD8+ T cell frequencies, IL-4, IL-10 and INF-γ levels was more significant in CAP + CSNP group than CAP group. CAP + CSNP is a promising new preparation of Schistosomal antigens that gave better results than immunization with CAP alone. CSNPs enhanced the immune and protective effect of CAP as validated by parasitological, histopathological and immunohistochemical studies. [ABSTRACT FROM AUTHOR]

Schistosomiasis and soil-transmitted helminthiasis remain a public health concern in Tanzania. This study investigated the prevalence and intensities of Schistosoma haematobium, S. mansoni, and soil-transmitted helminths and associated factors in Itilima district, north-western Tanzania. A cross-sectional survey was conducted between August and September 2020 among 3779 primary schoolchildren in 62 primary schools and 1122 adults in 19 villages. Urine samples were obtained from each participant and examined visually for the presence of macrohaematuria, microhaematuria, and S. haematobium eggs using a urine dipstick and urine filtration test. A single stool sample was obtained from each participant and screened for S. mansoni and soil-transmitted helminths using the Kato Katz and formalin-ether concentration techniques. A questionnaire was administered to schoolchildren to elucidate the risk factors for schistosomiasis. The overall prevalence of S. haematobium in adults was 8.1% (95% confidence interval (CI), 6.6–9.8%). In total, 3779 schoolchildren had complete results from urine testing, and the overall prevalence of S. haematobium was 10.1% (95% CI, 9.1–11.1%). The prevalence of S. mansoni and soil-transmitted helminths was relatively low among both children and adults compared to S. haematobium. Factors associated with S. haematobium infection among schoolchildren were the mother's occupation, children aged 11–15 years, and water contact behaviour. The odds of having schistosomiasis infection among children aged 11–15 are 40% higher than those aged 5–10 (95% confidence interval (CI), 10–80%, p = 0.04). Children of parents who are livestock keepers have 12.3 times higher odds of having infection compared to those who have small-scale businesses (95% CI, 1.0–5.4, p = 0.03). Children who are in contact with infested water more than three times a week have 2.1 times higher odds of having an infection compared to those who do not (95% CI, 2.1; 1.6–2.8, p < 0.001). The findings provide updated geographical information on prevalence, yielding insights into the planning and implementation of mass drug administration in rural Tanzania. [ABSTRACT FROM AUTHOR]

HIV and Schistosoma infections have been individually associated with pulmonary vascular disease. Co-infection with these pathogens is very common in tropical areas, with an estimate of six million people co-infected worldwide. However, the effects of HIV and Schistosoma co-exposure on the pulmonary vasculature and its impact on the development of pulmonary vascular disease are largely unknown. Here, we have approached these questions by using a non-infectious animal model based on lung embolization of Schistosoma mansoni eggs in HIV-1 transgenic (HIV) mice. Schistosome-exposed HIV mice but not wild-type (Wt) counterparts showed augmented pulmonary arterial pressure associated with markedly suppressed endothelial-dependent vasodilation, increased endothelial remodeling and vessel obliterations, formation of plexiform-like lesions and a higher degree of perivascular fibrosis. In contrast, medial wall muscularization was similarly increased in both types of mice. Moreover, HIV mice displayed an impaired immune response to parasite eggs in the lung, as suggested by decreased pulmonary leukocyte infiltration, small-sized granulomas, and augmented residual egg burden. Notably, vascular changes in co-exposed mice were associated with increased expression of proinflammatory and profibrotic cytokines, including IFN-γ and IL-17A in CD4+ and γδ T cells and IL-13 in myeloid cells. Collectively, our study shows for the first time that combined pulmonary persistence of HIV proteins and Schistosoma eggs, as it may occur in co-infected people, alters the cytokine landscape and targets the vascular endothelium for aggravated pulmonary vascular pathology. Furthermore, it provides an experimental model for the understanding of pulmonary vascular disease associated with HIV and Schistosoma co-morbidity.

BackgroundHelminth infections can modulate immunity to Mycobacterium tuberculosis (Mtb). However, the effect of helminths, including Schistosoma mansoni (SM), on Mtb infection outcomes is less clear. Furthermore, HIV is a known risk factor for tuberculosis (TB) disease and has been implicated in SM pathogenesis. Therefore, it is important to evaluate whether HIV modifies the association between SM and Mtb infection.SettingHIV-infected and HIV-uninfected adults were enrolled in Kisumu County, Kenya, between 2014 and 2017 and categorized into 3 groups based on Mtb infection status: Mtb-uninfected healthy controls, latent TB infection (LTBI), and active TB disease. Participants were subsequently evaluated for infection with SM.MethodsWe used targeted minimum loss estimation and super learning to estimate a covariate-adjusted association between SM and Mtb infection outcomes, defined as the probability of being Mtb-uninfected healthy controls, LTBI, or TB. HIV status was evaluated as an effect modifier of this association.ResultsSM was not associated with differences in baseline demographic or clinical features of participants in this study, nor with additional parasitic infections. Covariate-adjusted analyses indicated that infection with SM was associated with a 4% higher estimated proportion of active TB cases in HIV-uninfected individuals and a 14% higher estimated proportion of active TB cases in HIV-infected individuals. There were no differences in estimated proportions of LTBI cases.ConclusionsWe provide evidence that SM infection is associated with a higher probability of active TB disease, particularly in HIV-infected individuals.

Schistosome parasites infect more than 200 million people annually, mostly in sub-Saharan Africa, where people may be co-infected with more than one species of the parasite. Infection risk for any single species is determined, in part, by the distribution of its obligate intermediate host snail. As the World Health Organization reprioritizes snail control to reduce the global burden of schistosomiasis, there is renewed importance in knowing when and where to target those efforts, which could vary by schistosome species. This study estimates factors associated with schistosomiasis risk in 16 villages located in the Senegal River Basin, a region hyperendemic for Schistosoma haematobium and S. mansoni. We first analyzed the spatial distributions of the two schistosomes' intermediate host snails (Bulinus spp. and Biomphalaria pfeifferi, respectively) at village water access sites. Then, we separately evaluated the relationships between human S. haematobium and S. mansoni infections and (i) the area of remotely-sensed snail habitat across spatial extents ranging from 1 to 120 m from shorelines, and (ii) water access site size and shape characteristics. We compared the influence of snail habitat across spatial extents because, while snail sampling is traditionally done near shorelines, we hypothesized that snails further from shore also contribute to infection risk. We found that, controlling for demographic variables, human risk for S. haematobium infection was positively correlated with snail habitat when snail habitat was measured over a much greater radius from shore (45 m to 120 m) than usual. S. haematobium risk was also associated with large, open water access sites. However, S. mansoni infection risk was associated with small, sheltered water access sites, and was not positively correlated with snail habitat at any spatial sampling radius. Our findings highlight the need to consider different ecological and environmental factors driving the transmission of each schistosome species in co-endemic landscapes.

BackgroundTreatment of schistosomiasis, a neglected disease, relies on just one partially effective drug, praziquantel. We revisited the 9-acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound.MethodsRo 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice. We studied dose-response, hepatic shift and stage specificity. The metabolic stability of Ro 15-5458 was measured in the presence of human and mouse liver microsomes, and human hepatocytes; the latter also served to identify metabolites. Pharmacokinetic parameters were measured in naive mice. The efficacy of Ro 15-5458 was also assessed in S. haematobium-infected hamsters and S. japonicum-infected mice.ResultsRo 15-5458 had single-dose ED50 values of 15 and 5.3 mg/kg in mice harbouring juvenile and adult S. mansoni infections, respectively. An ED50 value of 17 mg/kg was measured in S. haematobium-infected hamsters; however, the compound was inactive at up to 100 mg/kg in S. japonicum-infected mice. The drug-induced hepatic shift occurred between 48 and 66 h post treatment. A single oral dose of 50 mg/kg of Ro 15-5458 had high activity against all tested S. mansoni stages (1-, 7-, 14-, 21- and 49-day-old). In vitro, human hepatocytes produced N-desethyl and glucuronide metabolites; otherwise Ro 15-5458 was metabolically stable in the presence of microsomes or whole hepatocytes. The maximum plasma concentration was approximately 8.13 μg/mL 3 h after a 50 mg/kg oral dose and the half-life was approximately 4.9 h.ConclusionsRo 15-5458 has high activity against S. mansoni and S. haematobium, yet lacks activity against S. japonicum, which is striking. This will require further investigation, as a broad-spectrum antischistosomal drug is desirable.

Background In Brazil, schistosomiasis mansoni cases still occur, even in non-endemic areas. This study aimed to evaluate schistosomiasis mansoni cases and to delimit water collections investigated for infested planorbidae in São Carlos, São Paulo, Brazil. Methods A cross-sectional descriptive study and spatial analysis of schistosomiasis mansoni cases notified in the city from January 2005 to December 2017 was conducted. The study used geographical information system software to map residential and leisure exposures to water courses and bodies and related them to planorbidae surveys of São Paulo state. Results During the study period, 32 cases were notified. The main forms were intestinal and hepatosplenic. Twenty-eight cases were allochthonous, two autochthonous and two indeterminate. Eleven patients (33.3%) had contact with water collections in São Carlos, mainly the 29 and Broa reservoirs. Three of them had contact only with water collections in the region. A third of cases lived in the Água Fria and Água Quente microbasins, highly impacted by the presence of domestic sewage, and the whole region seems to be colonized by Biomphalaria tenagophila. Conclusions The resolution of anthropogenic contamination of water bodies is crucial for controlling schistosomiasis mansoni autochthony in São Carlos. [ABSTRACT FROM AUTHOR]

Schistosomiasis is among the most common parasitic diseases in the world, with over 142 million people infected in low- and middle-income countries. Measuring population-level transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected using stool microscopy, which is logistically difficult at program scale and has low sensitivity when people have low infection burdens. We compared serological measures of transmission based on antibody response to S. mansoni soluble egg antigen (SEA) with stool-based measures of infection among 3,663 preschool-age children in an area endemic for S. mansoni in western Kenya. We estimated force of infection among children using the seroconversion rate and examined how it varied geographically and by age. At the community level, serological measures of transmission aligned with stool-based measures of infection (ρ = 0.94), and serological measures provided more resolution for between-community differences at lower levels of infection. Force of infection showed a clear gradient of transmission with distance from Lake Victoria, with 94% of infections and 93% of seropositive children in communities

Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.

Approximately 10% of the world's population is at risk of schistosomiasis, a disease of poverty caused by the Schistosoma parasite. To facilitate drug discovery for this complex flatworm, we developed an automated high-content screen to quantify the multidimensional responses of Schistosoma mansoni post-infective larvae (somules) to chemical insult. We describe an integrated platform to process worms at scale, collect time-lapsed, bright-field images, segment highly variable and touching worms, and then store, visualize, and query dynamic phenotypes. To demonstrate the methodology, we treated somules with seven drugs that generated diverse responses and evaluated 45 static and kinetic response descriptors relative to concentration and time. For compound screening, we used the Mahalanobis distance to compare multidimensional phenotypic effects induced by 1323 approved drugs. Overall, we characterize both known anti-schistosomals and identify new bioactives. Apart from facilitating drug discovery, the multidimensional quantification provided by this platform will allow mapping of chemistry to phenotype.

BackgroundOver the past five years, as a public service to encourage and accelerate drug discovery for diseases of poverty, the Medicines for Malaria Venture (MMV) has released box sets of 400 compounds named the Malaria, Pathogen and Stasis Boxes. Here, we screened the Pathogen Box against the post-infective larvae (schistosomula) of Schistosoma mansoni using assays particular to the three contributing institutions, namely, the University of California San Diego (UCSD) in the USA, the Swiss Tropical and Public Health Institute (Swiss TPH) in Switzerland, and the Fundação Oswaldo Cruz (FIOCRUZ) in Brazil. With the same set of compounds, the goal was to determine the degree of inter-assay variability and identify a core set of active compounds common to all three assays. New drugs for schistosomiasis would be welcome given that current treatment and control strategies rely on chemotherapy with just one drug, praziquantel.MethodsBoth the UCSD and Swiss TPH assays utilize daily observational scoring methodologies over 72 h, whereas the FIOCRUZ assay employs XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) at 72 h to measure viability as a function of NAD+/NADH redox state. Raw and transformed data arising from each assay were assembled for comparative analysis.ResultsFor the UCSD and Swiss TPH assays, there was strong concordance of at least 87% in identifying active and inactive compounds on one or more of the three days. When all three assays were compared at 72 h, concordance remained a robust 74%. Further, robust Pearson's correlations (0.48-0.68) were measured between the assays. Of those actives at 72 h, the UCSD, Swiss TPH and FIOCRUZ assays identified 86, 103 and 66 compounds, respectively, of which 35 were common. Assay idiosyncrasies included the identification of unique compounds, the differential ability to identify known antischistosomal compounds and the concept that compounds of interest might include those that increase metabolic activity above baseline.ConclusionsThe inter-assay data generated were in good agreement, including with previously reported data. A common set of antischistosomal molecules for further exploration has been identified .

Abstract Background In the past decade, Brazil has significantly reduced the prevalence of schistosomiasis through a combined effort of early treatment of infected people, expansion of basic sanitation infrastructure and educational measures. Despite these efforts, in some areas, prevalence of schistosomiasis exceeds 20% of the school population, who lack knowledge of the risks of the disease. Action can be taken in schools to empower this population about their health condition. This paper describes the role of the teacher as a multiplier of knowledge about schistosomiasis and proposes two different approaches to training these teachers. Methods This study used mixed methods to evaluate training of teachers and educational intervention with those teachers’ pupils. Two training courses, each with 40 h of face-to-face activity, were offered to 19 teachers, using two different but complementary approaches, based on theoretical references and specific educational strategies: Critical Pedagogical Approach (Training Course I, held in 2013) and Creative Play Approach (Training Course II, held in 2014).The courses included classroom activities, laboratory and field work. After the training, the teachers conducted activities on schistosomiasis with their pupils. These activities involved constructing educational materials and cultural productions. The pupils’ knowledge about the disease was evaluated before the activities and 12 months later. The teachers’ acceptance and perceptions were assessed through structured interviews and subsequent thematic analysis. The Shistosoma mansoni infection status of teachers and their students was also assessed using the Kato Katz stool test. Results The parasitological study showed 31.6% of the teachers and 21.4% of the pupils to be positive for S. mansoni. The teachers’ knowledge of important aspects of schistosomiasis transmission and prevention was fragmented and incorrect prior to the training. The teachers’ knowledge changed significantly after the training and they were strongly accepting of the pedagogical methods used during the training. The level of their pupils’ knowledge about the disease had increased significantly (p 0.05). Conclusions The results of this study underline the importance of schools and teachers as partners in controlling and eliminating schistosomiasis. Teacher training on the disease significantly increases their pupils’ knowledge, reflecting empowerment with regard to local health conditions.

Objective. To investigate the relationship between the prevalence of schistosomiasis and soil-transmitted helminthiasis with variables related to access to water, sanitation and solid waste in Latin American and Caribbean (LAC) countries. Method. A systematic review was performed in the LILACS, PubMed, Web of Science, and SciELO databases. Studies published between 1950 and August 2021, with an ecological design and a focus on population groups (states, municipalities and/or districts), having the prevalence of infection by Schistosoma mansoni, Ancylostoma sp., Necator americanus, Ascaris lumbricoides or Trichuris trichiura as primary variable and access to water, sewage and/or solid waste as explanatory variables were included. Open access articles with full text available in English, Spanish, or Portuguese were considered. The risk of bias and the quality of the studies were assessed according to the Joanna Briggs Institute manual. Results. Of 2 714 articles, nine were eligible, published between 1994 and 2021 and covering 22 LAC countries and 14 350 municipalities. All articles had moderate methodological quality. Environmental variables indicated an association between water supply and solid waste collection with schistosomiasis; water supply with ascariasis, trichuriasis and hookworm; and sewage with ascariasis and hookworm. Except for one article, which had regional coverage for LAC, all the others were developed in Brazil. Conclusion. There is a clear need to expand research on the association between household and collective health conditions and parasitic diseases for all endemic countries in LAC to support environmental strategies to control these diseases. [ABSTRACT FROM AUTHOR]

Schistosomiasis mansoni leads to liver fibrosis that was believed to be irreversible once established leading to life-threatening complications in most cases. Praziquantel (PZQ) is considered the best drug in treatment, for decades. A universal approach towards drug repurposing is recommended, to be combined with other known drugs that may expand their efficiencies or/and discover new mechanisms of action of the used drugs. In this work Angiotensin-converting enzyme inhibitor (ACEI) "Lisinopril" was used alone or with Praziquantel (PZQ), versus long-duration PZQ (LD-PZQ) to test for their anti-fibrotic properties, applying Transforming Growth factor beta 1 (TGF-β1) as an indicator of activated fibrotic fibroblasts, to be automatically quantified within hepatic tissues of experimentally infected mice, using a software image analyzer. All treated groups showed significant reduction within TGF-β1 local hepatic expression, with the greatest reduction occurring among groups treated with LD-PZQ followed by those which received combined ACEI and PZQ. The highest TGF-β1 local hepatic expression values were obtained by groups receiving the classic anti-bilharzial single oral dose praziquantel (S.O.D PZQ) regimen, indicating its ineffectiveness as a monotherapeutic agent to minimize liver fibro-sclerotic threats in acute and chronic phases of schistosomiasis. Lisinopril alone or when combined with PZQ, succeeded in causing a drop in TGF-β1 hepatic expression as LD-PZQ regimen, thus increasing the chance of healing without hepatic scarring. Yet, its usage as an adjuvant to PZQ, instead of LD-PZQ has the additional benefit of not exposing the community to unwarranted resistance to PZQ, a drug that is to date still indispensable for the treatment of bilharziasis. [ABSTRACT FROM AUTHOR]

Schistosomiasis is one of the most important human helminthiases worldwide. Praziquantel is the current treatment, and no vaccine is available until the present. Thus, the presented study aimed to evaluate the immunization effects with recombinant Schistosoma mansoni enzymes: Adenosine Kinase (AK) and Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT), as well as a MIX of the two enzymes. Female Balb/c mice were immunized in three doses, and 15 days after the last immunization, animals were infected with S. mansoni. Our results showed that the group MIX presented a reduction in the eggs in feces by 30.74% and 29%, respectively, in the adult worms. The groups AK, HGPRT and MIX could produce IgG1 antibodies, and the groups AK and MIX produced IgE antibodies anti-enzymes and anti-S. mansoni total proteins. The groups AK, HGPRT and MIX induced a reduction in the eosinophils in the peritoneal cavity. Besides, the group AK showed a decrease in the number of hepatic granulomas (41.81%) and the eggs present in the liver (42.30%). Therefore, it suggests that immunization with these enzymes can contribute to schistosomiasis control, as well as help to modulate experimental infection inducing a reduction of physiopathology in the disease. [ABSTRACT FROM AUTHOR]

Schistosomiasis and soil-transmitted helminthiasis remain a public health concern in Tanzania. This study investigated the prevalence and intensities of Schistosoma haematobium, S. mansoni, and soil-transmitted helminths and associated factors in Itilima district, north-western Tanzania. A cross-sectional survey was conducted between August and September 2020 among 3779 primary schoolchildren in 62 primary schools and 1122 adults in 19 villages. Urine samples were obtained from each participant and examined visually for the presence of macrohaematuria, microhaematuria, and S. haematobium eggs using a urine dipstick and urine filtration test. A single stool sample was obtained from each participant and screened for S. mansoni and soil-transmitted helminths using the Kato Katz and formalin-ether concentration techniques. A questionnaire was administered to schoolchildren to elucidate the risk factors for schistosomiasis. The overall prevalence of S. haematobium in adults was 8.1% (95% confidence interval (CI), 6.6–9.8%). In total, 3779 schoolchildren had complete results from urine testing, and the overall prevalence of S. haematobium was 10.1% (95% CI, 9.1–11.1%). The prevalence of S. mansoni and soil-transmitted helminths was relatively low among both children and adults compared to S. haematobium. Factors associated with S. haematobium infection among schoolchildren were the mother’s occupation, children aged 11–15 years, and water contact behaviour. The odds of having schistosomiasis infection among children aged 11–15 are 40% higher than those aged 5–10 (95% confidence interval (CI), 10–80%, p = 0.04). Children of parents who are livestock keepers have 12.3 times higher odds of having infection compared to those who have small-scale businesses (95% CI, 1.0–5.4, p = 0.03). Children who are in contact with infested water more than three times a week have 2.1 times higher odds of having an infection compared to those who do not (95% CI, 2.1; 1.6–2.8, p < 0.001). The findings provide updated geographical information on prevalence, yielding insights into the planning and implementation of mass drug administration in rural Tanzania.

Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100 mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by ≥ 90% and ≥46% (mature), and ≥89% and ≥79% (juvenile), respectively. In contrast, PZQ decreased mature female and male worm burdens by 95% and 94%, respectively, but was ineffective against juvenile stages. Against 7-day-old lung-stage worms, TPT sulfonate was only effective at twice the dose decreasing female and male burdens by 95 and 80%, respectively. Single oral doses at 400 and/or 600 mg/kg across various developmental time-points (1-, 7-, 15-, 21- and/or 42 day-old) were consistent with the QD x4 data; efficacy was strongest once the parasites had completed lung migration, and female and male burdens were decreased by at least 90% and 80%, respectively. In vitro, TPT sulfonate is inactive against the parasite suggesting a pro-drug mechanism of action. In mice, TPT sulfonate is fully absorbed and subject to rapid, non-CYP-mediated, first-pass metabolism that is initiated by desulfation and yields a series of metabolites. The initially-formed free thiol-containing metabolite, termed TP thiol, was chemically synthesized; it dose-dependently decreased S. mansoni and Schistosoma haematobium motility in vitro. Also, when administered as a single 50 mg/kg IP dose, TP thiol decreased 33-day-old S. mansoni female and male burdens by 35% and 44%, with less severe organomegaly. Overall, TPT sulfonate's efficacy profile is competitive with that of PZQ. Also, the characterization of a parasiticidal metabolite facilitates an understanding and improvement of the chemistry, and identification of the mechanism of action and/or target.

Background: In the past decade, Brazil has significantly reduced the prevalence of schistosomiasis through a combined effort of early treatment of infected people, expansion of basic sanitation infrastructure and educational measures. Despite these efforts, in some areas, prevalence of schistosomiasis exceeds 20% of the school population, who lack knowledge of the risks of the disease. Action can be taken in schools to empower this population about their health condition. This paper describes the role of the teacher as a multiplier of knowledge about schistosomiasis and proposes two different approaches to training these teachers.Methods: This study used mixed methods to evaluate training of teachers and educational intervention with those teachers' pupils. Two training courses, each with 40 h of face-to-face activity, were offered to 19 teachers, using two different but complementary approaches, based on theoretical references and specific educational strategies: Critical Pedagogical Approach (Training Course I, held in 2013) and Creative Play Approach (Training Course II, held in 2014).The courses included classroom activities, laboratory and field work. After the training, the teachers conducted activities on schistosomiasis with their pupils. These activities involved constructing educational materials and cultural productions. The pupils' knowledge about the disease was evaluated before the activities and 12 months later. The teachers' acceptance and perceptions were assessed through structured interviews and subsequent thematic analysis. The Shistosoma mansoni infection status of teachers and their students was also assessed using the Kato Katz stool test.Results: The parasitological study showed 31.6% of the teachers and 21.4% of the pupils to be positive for S. mansoni. The teachers' knowledge of important aspects of schistosomiasis transmission and prevention was fragmented and incorrect prior to the training. The teachers' knowledge changed significantly after the training and they were strongly accepting of the pedagogical methods used during the training. The level of their pupils' knowledge about the disease had increased significantly (p < 0.05). However, pupils responded that, even after the educational activities, they still had contact with the city's contaminated waters (p > 0.05).Conclusions: The results of this study underline the importance of schools and teachers as partners in controlling and eliminating schistosomiasis. Teacher training on the disease significantly increases their pupils' knowledge, reflecting empowerment with regard to local health conditions. [ABSTRACT FROM AUTHOR]

BackgroundSerine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis.Methodology/principal findingsSmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting.Conclusions/significanceThe data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer - (R)-PZQ - which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.

Introduction: Human and animal studies have shown that schistosomiasis protects against metabolic diseases such as dyslipidemia, atherosclerosis and diabetes. Objectives: However, less is known about the effects of a high-fat diet on hepatic architecture, formation and composition of granulomas in acute schistosomiasis mansoni. Methods: Male C57BL/6 mice fed high-fat (60% fat) chow or standard (10% fat) chow for 13 weeks were infected with 80 Schistosoma mansoni cercariae. The mice were assigned into four groups: uninfected fed standard (SC), high-fat chow (HFC), infected fed standard (ISC) and high-fat chow (IHFC). Blood lipid concentrations (cholesterol, triglycerides, LDL, VLDL, HDL), oral glucose tolerance test, body mass gain, liver mass and intestinal parasite egg counting (oogram), cellular composition, percentage of inflammatory infiltrates and morphometric features (area and perimeter) of liver granulomas were measured. The volumetric density of hepatocytes, steatosis, sinusoids, necrosis and hepatic fibrosis were estimated by using stereology. Results: IHFC mice showed lower blood lipid levels, biometrics, improved glucose tolerance and less steatosis compared to control mice (HFC). The IHFC group showed larger granulomas, predominance of polymorphonuclear cells and rich inflammatory infiltration, binucleated hepatocytes and histopathological changes more severe than ISC. Conclusion: Although acute schistosomiasis reduces the effects of a high-fat diet on the host's metabolism, it induces damage to liver architecture. [ABSTRACT FROM AUTHOR]

Solid-organ transplantation procedures have witnessed a surge in frequency. Consequently, increased attention to associated infections and their impact on graft success is warranted. The liver is the principal target for infection by the flatworm Schistosoma mansoni. Hence, rigorous screening protocols for this parasite should be implemented for liver transplantation donors and recipients. This study investigated the risks posed by schistosomiasis-infected liver tissues for successful liver transplantation (LT), considering donors and recipients, by analyzing reported cases. Among the 43 patients undergoing LT (donors = 19; recipients = 24), 32 were infected with S. mansoni, five were infected with other Schistosoma species, and no identification was made in four patients. Reported follow-up periods ranged from 1 to 132 months, and all patients achieved successful recovery. As these helminths do not replicate in their vertebrate hosts, immunosuppressive treatment is not expected to promote increased morbidity or reactivation. Moreover, suspected or confirmed schistosomiasis infections often have a benign course, and generally, should not prevent LT. The available literature was reviewed and a provisional screening protocol has been proposed.

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis.

Schistosomiasis is one of the most important human helminthiases worldwide. Praziquantel is the current treatment, and no vaccine is available until the present. Thus, the presented study aimed to evaluate the immunization effects with recombinant Schistosoma mansoni enzymes: Adenosine Kinase (AK) and Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT), as well as a MIX of the two enzymes. Female Balb/c mice were immunized in three doses, and 15 days after the last immunization, animals were infected with S. mansoni. Our results showed that the group MIX presented a reduction in the eggs in feces by 30.74% and 29%, respectively, in the adult worms. The groups AK, HGPRT and MIX could produce IgG1 antibodies, and the groups AK and MIX produced IgE antibodies anti-enzymes and anti-S. mansoni total proteins. The groups AK, HGPRT and MIX induced a reduction in the eosinophils in the peritoneal cavity. Besides, the group AK showed a decrease in the number of hepatic granulomas (41.81%) and the eggs present in the liver (42.30%). Therefore, it suggests that immunization with these enzymes can contribute to schistosomiasis control, as well as help to modulate experimental infection inducing a reduction of physiopathology in the disease.

Background Periportal fibrosis (PPF) is the major pathological consequence of Schistosoma mansoni infection. The Coutinho index—the alkaline phosphatase (ALP) to platelet ratio ([ALP/upper limit of normality {ULN}]/platelet count [106/L] x 100)—was validated. Validation consisted of modest laboratory tests to predict advanced PPF. Methods A total of 378 individuals from an endemic area of Brazil with a previous history of the disease and/or a positive parasitological examination were evaluated. We used ultrasound examination as the gold standard for classification of the PPF pattern and measured the biological markers of the index. Results Forty-one individuals (10.8%) without PPF, 291 (77%) with moderate PPF and 46 (12.2%) with advanced PPF, were identified. ALP and platelet count were used for the index. The cut-off point ≥0.228 predicted the presence of fibrosis with an area under the receiver operating characteristic curve (AUROC) of 0.56, sensitivity of 68.6% and specificity of 46.3%. There was an absence of PPF in 46.3% of individuals without fibrosis and the presence of PPF in 68.5% of cases with moderate and advanced ultrasound fibrosis. The identification of advanced fibrosis with a cut-off point ≥0.316 revealed an AUROC curve of 0.70, sensitivity of 67.4% and specificity of 68.3%, thus confirming the advanced phase in 65.2% of cases compared with ultrasound. Conclusion The Coutinho index was able to predict advanced PPF in most individuals. It is valid as a new tool, uses routine laboratory tests and therefore is more accessible for screening patients with a severe form of the disease in endemic areas. [ABSTRACT FROM AUTHOR]

Schistosomiasis is one of a number of chronic helminth diseases of poverty that severely impact personal and societal well-being and productivity. Peptidases (proteases) are vital to successful parasitism, and can modulate host physiology and immunology. Interference of peptidase action by specific drugs or vaccines can be therapeutically beneficial. To date, research on peptidases in the schistosome parasite has focused on either the functional characterization of individual peptidases or their annotation as part of global genome or transcriptome studies. We were interested in functionally characterizing the complexity of peptidase activity operating at the host-parasite interface, therefore the excretory-secretory products of key developmental stages of Schistosoma mansoni that parasitize the human were examined. Using class specific peptidase inhibitors in combination with a multiplex substrate profiling assay, a number of unique activities derived from endo- and exo-peptidases were revealed in the excretory-secretory products of schistosomula (larval migratory worms), adults and eggs. The data highlight the complexity of the functional degradome for each developmental stage of this parasite and facilitate further enquiry to establish peptidase identity, physiological and immunological function, and utility as drug or vaccine candidates.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design.

RationaleThe etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-β signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.ObjectivesWe hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-β-dependent vascular remodeling.MethodsWild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed.Measurements and main resultsMice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-β activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation.ConclusionsCombined IL-4 and IL-13 deficiency is required for protection against TGF-β-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.

Schistosomiasis Mansoni is endemic in approximately 76 countries and it currently affects 8 million Brazilian posing a serious threat to our country health system and population. The parasite Schistosoma Mansoni has the Biomphalaria Mollusc as its intermediate host and their infected larvae, is responsible for transmitting the disease to the population when they are released in the water. People in contact with water infested by larvae are prone to catch this dangerous disease. Our study was conducted in three different areas of lagoon do Retiro, nearby the city of Junqueiro- Al, Brazil. Molluscs were collected with the help of a special sieve, then kept in plastic containers identified by the area and sent to the State University of Alagoas( Uneal) laboratory, in Campus 1. There they were isolated and studied in a petri dish containing 10 ml of dechlorinated water and exposed to a 40 W incandescent lamp. For the molluscs that did not promptly test positive for the Schistosoma Mansoni, the exposure was repeated in the space if 7, 15 and 30 days, in order to rule out the possibility of infection. Out of the 3 areas studied in 2018 one tested positive with a total of 8 infected molluscs. The study therefore proved the lagoon is not safe to swim, bathe, or have its water used by the population and the public heath departament should alert the local population about this danger and health risc.

ABSTRACT Background: The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy. However, studies have shown varices recurrence especially after long-term follow-up. Aim: To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS. Methods: Thirty-six patients submitted to EGDS were followed for more than five years. They were divided into two groups, according to the portal pressure drop, more or less than 30%, and compared with the behavior of esophageal varices and the rate of bleeding recurrence. Results: A significant reduction on the early and late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy. Conclusion: The drop in portal pressure did not significantly influence the variation of variceal calibers when comparing pre-operative and early or late post-operative diameters. The comparison between the portal pressure drop and the rebleeding rates was also not significant.

Schistosoma japonicum is endemic in the Philippines. The Kato-Katz (KK) method was used to diagnose S. japonicum. This is impractical, particularly when the sample size is limited. Knowledge on point-of-care circulating cathodic antigen (CCA) test performance for S. japonicum is limited. Determining the sensitivity and specificity of new diagnostics is difficult when the gold standard test is less effective or absent. Latent class analysis (LCA) can address some limitations. A total of 484 children and 572 adults from the Philippines were screened for S. japonicum. We performed Bayesian LCA to estimate the infection prevalence, sensitivity and specificity of each test by stratifying them into two age groups. Observed prevalence assessed by KK was 50.2% and 31.8%, and by CCA was 89.9% and 66.8%, respectively. Using Bayesian LCA, among children, the sensitivity and specificity of CCA were 94.8% (88.7-99.4) and 21.5% (10.5-36.1) while those of KK were 66.0% (54.2-83.3) and 78.1% (61.1-91.3). Among adults, the sensitivity and specificity of CCA were 86.4% (76.6-96.9) and 62.8% (49.1-81.1) while those of KK were 43.6% (35.1-53.9) and 85.5% (75.8-94.6). Overall, CCA was more sensitive than KK, regardless of the age group at diagnosis, as KK was more specific. KK and CCA have different diagnostic performance, which should inform their use in the planning and implementation of S. japonicum control programs., (© 2024. The Author(s).)

Schistosomiasis is a major public health problem in tropical areas of the world. Health-related quality of life (HRQOL) measurement is being widely used to evaluate the impact of a disease or treatment in several aspects of daily life. However, few studies evaluated the impact of severe forms of schistosomiasis on HRQOL of affected individuals and compared them to healthy controls with a similar socio-demographic background. Our aims were to evaluate the HRQOL in patients with hepatosplenic schistosomiasis (HS) and schistosomal myeloradiculopathy (SMR) and healthy volunteers (HV) and determine if clinical complications of the disease are associated with HRQOL scores. We interviewed and evaluated the HRQOL in 49 patients with HS, 22 patients with SMR, and 26 HV from an outpatient clinic of the Federal University of Minas Gerais University Hospital using the WHOQOL-BREF questionnaire. SMR and HS patients had a significantly lower overall quality of life score when comparing with the HV control group (p = 0.003 and p = 0.005, respectively). Multivariate ordinal regression model adjusted for sex, age, and educational level indicated that HS and SMR patients have three and five times more chances of having a lower quality of life than healthy volunteers (Odds Ratio 3.13 and 5.04, respectively). There was no association between complications of HS disease and quality of life scores. In contrast, worse quality of life was observed in SMR patients that presented back or leg pain, leg paresthesia, and bladder dysfunction. In conclusion, HS and SMR significantly impact the overall quality of life of the affected individuals, reinforcing the importance of efforts to control and eradicate this debilitating disease and suggesting that multidisciplinary clinical management of schistosomiasis patients would be more appropriate and could potentially improve patient's quality of life.

Background: Colorectal cancer is one of the most common cancers in men and women worldwide. There are several studies showing an association between chronic schistosomiasis infection and colorectal cancer. Case Report: A 53-year-old woman presented with recurrent metastatic colon cancer involving the peritoneum and bilateral adnexa. The patient then underwent exploratory laparotomy that involved abdominal wall deposit resection, omentectomy, redo left hemicolectomy, peritonectomy, diaphragmatic stripping, and total abdominal hysterectomy with bilateral salpingectomy-oophorectomy, as well as hyperthermic intraperitoneal chemotherapy (HIPEC). She also underwent adjuvant chemotherapy, but on her 6th cycle, the patient suffered intolerable anal pain, diarrhea, and rectal bleeding. Her colonoscopy showed extended circumferential inflammation with loses of vascular pattern and a few rectal ulcers going up to the anastomosis site. Biopsy revealed Schistosoma mansoni eggs and marked ischemic changes. She was then managed with a single dose of Praziquantel. Conclusions: Colorectal schistosomiasis infection is a rare cause of such common presentations especially in postoperative settings in a patient with recurrent metastatic colon cancer. The use of multimodality investigations and high clinical suspicion were needed for the diagnosis and to exclude other common etiologies. [ABSTRACT FROM AUTHOR]

The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although the amino acid sequence of SmARG is only 42% identical with that of human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2(S)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide a proof of concept for this approach in the enhancement of enzyme-inhibitor affinity.

Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.

Abstract Purpose: To evaluate a possible relationship between the size of the spleen and values of circulating blood elements in patients with schistosomatic splenomegaly. Methods: ixty one patients with hepatosplenic schistosomiasis mansoni underwent a clinical exam and peripheral venous blood was collected for a hemogram. The erythrocyte, hemoglobin, hematocrit, leukocyte, and platelet values were determined. All patients underwent abdominal ultrasound to measure the spleen. The hematological test results were compared to the size of the spleen. Results: The size of the spleen varied from 14.0 to 28.4 (19.9 ± 3.7) cm according to the ultrasound image. Thrombocytopenia was observed 58 (95%) patients, leukopenia in 55 (90%) patients, and anemia in 32 (52.4%) patients. Leukopenia was proportional to splenomegaly. Conclusion: Schistosomal splenomegaly leads to leukopenia in direct proportion to the size of the spleen.

Abstract INTRODUCTION Suckling by schistosomotic mice improves anti-ovalbumin (OA) antibody production, while delayed-type hypersensitivity (DTH) remains unaffected. This property of milk from schistosomotic mice was investigated in IL-12/IL-23-deficient mice (IL-12p40KO). METHODS We compared anti-OA DTH, IgG2a and cytokines in wild-type and IL-12p40KO mice suckled by infected (SIM) or non-infected (CONTROL) mothers. RESULTS SIM mice showed similar intensity and eosinophils in the DTH, which was abolished in IL-12p40KO and IL-12p40KO-SIM mice. In IL-12p40KO-SIM, IgG2a and TGF-β levels were higher, but IL-6 levels were lower. CONCLUSIONS Milk from schistosomotic mothers may evoke IgG2a without eliciting DTH in IL-12/IL-23 deficiencies, by changing TGF-β/IL-6 levels.