CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children.

Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7-15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.

Therapeutic efficacy of candidate antischistosomal drugs in a murine model of schistosomiasis mansoni.

Schistosomiasis is a neglected tropical disease associated with considerable morbidity. Praziquantel (PZQ) is effective against adult schistosomes, yet, it has little effect on juvenile stages, and PZQ resistance is emerging. Adopting the drug repurposing strategy as well as assuming enhancing the efficacy and lessening the doses and side effects, the present study aimed to investigate the in vivo therapeutic efficacy of the widely used antiarrhythmic, amiodarone, and diuretic, spironolactone, and combinations of them compared to PZQ. Mice were infected by Schistosoma mansoni "S. mansoni" cercariae (Egyptian strain), then they were divided into two major groups: Early- [3 weeks post-infection (wpi)] and late- [6 wpi] treated. Each group was subdivided into seven subgroups: positive control, PZQ, amiodarone, spironolactone, PZQ combined with amiodarone, PZQ combined with spironolactone, and amiodarone combined with spironolactone-treated groups. Among the early-treated groups, spironolactone had the best therapeutic impact indicated by a 69.4% reduction of total worm burden (TWB), 38.6% and 48.4% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 49%. Whereas, among the late-treated groups, amiodarone combined with PZQ was superior to PZQ alone evidenced by 96.1% reduction of TWB with the total disappearance of female and copula in the liver and intestine, 53.1% and 84.9% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 67.6%. Comparatively, spironolactone was superior to PZQ and amiodarone in the early treatment phase targeting immature stages, while amiodarone had a more potent effect when combined with PZQ in the late treatment phase targeting mature schistosomes.

Dual Strategy to Design New Agents Targeting Schistosoma mansoni: Advancing Phenotypic and SmCB1 Inhibitors for Improved Efficacy.

In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm Schistosoma mansoni and its target protease S. mansoni cathepsin B1 (SmCB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds' in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in S. mansoni newly transformed schistosomula (NTS), adult worms, and SmCB1 inhibition. The optimized compounds from both approaches ("phenotypic" vs "SmCB1" approach) demonstrated improved efficacy against S. mansoni NTS and adult worms, with 2h from the "SmCB1" approach emerging as the most potent compound. 2h displayed nanomolar inhibition of SmCB1 (Ki = 0.050 µM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound 2h toward S. mansoni adults (86% dead worms at 10 µM, 68% at 1 µM, 35% at 0.1 µM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.

Improving the Cost-efficiency of Preventive Chemotherapy: Impact of New Diagnostics on Stopping Decisions for Control of Schistosomiasis.

BACKGROUND: Control of schistosomiasis (SCH) relies on the regular distribution of preventive chemotherapy (PC) over many years. For the sake of sustainable SCH control, a decision must be made at some stage to scale down or stop PC. These "stopping decisions" are based on population surveys that assess whether infection levels are sufficiently low. However, the limited sensitivity of the currently used diagnostic (Kato-Katz [KK]) to detect low-intensity infections is a concern. Therefore, the use of new, more sensitive, molecular diagnostics has been proposed. METHODS: Through statistical analysis of Schistosoma mansoni egg counts collected from Burundi and a simulation study using an established transmission model for schistosomiasis, we investigated the extent to which more sensitive diagnostics can improve decision making regarding stopping or continuing PC for the control of S. mansoni. RESULTS: We found that KK-based strategies perform reasonably well for determining when to stop PC at a local scale. Use of more sensitive diagnostics leads to a marginally improved health impact (person-years lived with heavy infection) and comes at a cost of continuing PC for longer (up to around 3 years), unless the decision threshold for stopping PC is adapted upward. However, if this threshold is set too high, PC may be stopped prematurely, resulting in a rebound of infection levels and disease burden (+45% person-years of heavy infection). CONCLUSIONS: We conclude that the potential value of more sensitive diagnostics lies more in the reduction of survey-related costs than in the direct health impact of improved parasite control.

How Does Treatment Coverage and Proportion Never Treated Influence the Success of Schistosoma mansoni Elimination as a Public Health Problem by 2030?

BACKGROUND: The 2030 target for schistosomiasis is elimination as a public health problem (EPHP), achieved when the prevalence of heavy-intensity infection among school-aged children (SAC) reduces to <1%. To achieve this, the new World Health Organization guidelines recommend a broader target of population to include pre-SAC and adults. However, the probability of achieving EPHP should be expected to depend on patterns in repeated uptake of mass drug administration by individuals. METHODS: We employed 2 individual-based stochastic models to evaluate the impact of school-based and community-wide treatment and calculated the number of rounds required to achieve EPHP for Schistosoma mansoni by considering various levels of the population never treated (NT). We also considered 2 age-intensity profiles, corresponding to a low and high burden of infection in adults. RESULTS: The number of rounds needed to achieve this target depends on the baseline prevalence and the coverage used. For low- and moderate-transmission areas, EPHP can be achieved within 7 years if NT ≤10% and NT <5%, respectively. In high-transmission areas, community-wide treatment with NT <1% is required to achieve EPHP. CONCLUSIONS: The higher the intensity of transmission, and the lower the treatment coverage, the lower the acceptable value of NT becomes. Using more efficacious treatment regimens would permit NT values to be marginally higher. A balance between target treatment coverage and NT values may be an adequate treatment strategy depending on the epidemiological setting, but striving to increase coverage and/or minimize NT can shorten program duration.

Efficacy and safety of prazequantel for the treatment of Schistosoma mansoni infection across different transmission settings in Amhara Regional State, northwest Ethiopia.

BACKGROUND: Schistosoma mansoni and S. haematobium infections have been public health problems in Ethiopia, S. mansoni being more prevalent. To reduce the burden of schistosomiasis, a national school-based prazequantel (PZQ) mass drug administration (MDA) program has been implemented since November 2015. Nevertheless, S. mansoni infection is still a major public health problem throughout the country. Reduced efficacy of PZQ is reported by a few studies in Ethiopia, but adequate data in different geographical settings is lacking. Hence, this study aimed to assess the efficacy and safety of PZQ for the treatment of S. mansoni infection across different transmission settings in Amhara Regional State, northwest Ethiopia. METHODS: A school-based single-arm prospective cohort study was conducted from February to June, 2023 among 130 S. mansoni-infected school-aged children (SAC). Forty-two, 37, and 51 S. mansoni-infected SAC were recruited from purposely selected schools located in low, moderate, and high transmission districts, respectively. School-aged children who were tested positive both by Kato Katz (KK) using stool samples and by the point of care circulating cathodic antigen (POC-CCA) test using urine samples at baseline were treated with a standard dose of PZQ and followed for 21 days for the occurrence of adverse events. After three weeks post-treatment, stool and urine samples were re-tested using KK and POC-CCA. Then the cure rate (CR), egg reduction rate (ERR), and treatment-associated adverse events were determined. The data were analyzed using SPSS version 21. RESULTS: Out of the total 130 study participants, 110 completed the follow-up. The CR and ERR of PZQ treatment were 88.2% (95%CI: 82.7-93.6) and 93.5% (95%CI: 85.4-98.5), respectively, by KK. The CR of PZQ based on the POC-CCA test was 70.9% (95%CI: 62.7-79.1) and 75.5% (95%CI: 67.3-83.6) depending on whether the interpretation of 'trace' results was made as positive or negative, respectively. After treatment on the 21st day, 78 and 83 participants tested negative both by KK and POC-CCA, with respective interpretations of 'trace' POC-CCA test results as positive or negative. The CR in low, moderate and high transmission settings was 91.7%, 91.2% and 82.5%, respectively (p = 0.377) when evaluated by KK. The CR among SAC with a light infection at baseline (95.7%) by KK was higher than that of moderate (81.5%) and heavy (64.3%) infections (χ2 = 12.53, p = 0.002). Twenty-six (23.6%) participants manifested at least one adverse event. Eleven (10.0%), eight (7.3%), six (5.5%), and three (2.7%) participants complained about abdominal pain, nausea, headache, and anorexia, respectively. All adverse events were mild, needing no intervention. Occurrence of adverse events was slightly higher in high endemic areas (32.5%) than moderate (23.5%) and low endemic areas (p = 0.279). CONCLUSIONS: A single dose of 40 mg/kg PZQ was efficacious and safe for the treatment of S. mansoni infection when it was evaluated by the KK test, but a lower efficacy was recorded when it was evaluated by the POC-CCA test. However, the POC-CCA test's specificity, clearance time of CCA from urine after treatment, and interpretation of weakly reactive (trace) test results need further research.

Potential i-Nos/Arg-1 Switch with NLRP3 and Parasitic Load Down Regulation in Experimental Schistosoma mansoni Infection via Chloroquine Repurposing.

In previous studies, the inhibitory effect of chloroquine on NLRP3 inflammasome and heme production was documented. This may be employed as a double-bladed sword in schistosomiasis (anti-inflammatory and parasiticidal). In this study, chloroquine's impact on schistosomiasis mansoni was investigated. The parasitic load (worm/egg counts and reproductive capacity index [RCI]), i-Nos/Arg-1 expression, splenomegaly, hepatic insult and NLRP3-immunohistochemical expression were assessed in infected mice after receiving early and late repeated doses of chloroquine alone or dually with praziquantel. By early treatment, the least RCI was reported in dually treated mice (41.48 ± 28.58) with a significant reduction in worm/egg counts (3.50 ± 1.29/2550 ± 479.58), compared with either drug alone. A marked reduction in the splenic index was achieved by prolonged chloroquine administration (alone: 43.15 ± 5.67, dually: 36.03 ± 5.27), with significantly less fibrosis (15 ± 3.37, 14.25 ± 2.22) than after praziquantel alone (20.5 ± 2.65). Regarding inflammation, despite the praziquantel-induced significant decrease in NLRP3 expression, the inhibitory effect was marked after dual and chloroquine administration (liver: 3.13 ± 1.21/3.45 ± 1.23, spleen: 5.7 ± 1.6/4.63 ± 2.41). i-Nos RNA peaked with early/late chloroquine administration (liver: 68.53 ± 1.8/57.78 ± 7.14, spleen: 63.22 ± 2.06/62.5 ± 3.05). High i-Nos echoed with a parasiticidal and hepatoprotective effect and may indicate macrophage-1 polarisation. On the flip side, the chloroquine-induced low Arg-1 seemed to abate immune tolerance and probably macrophage-2 polarisation. Collectively, chloroquine synergised the praziquantel-schistosomicidal effect and minimised tissue inflammation, splenomegaly and hepatic fibrosis.

Efficacy of a Single Oral Dose of Artesunate plus Sulfalene-Pyrimethamineversus Praziquantel in the Treatment of Schistosoma mansoni in Kenyan Children: An Open-Label, Randomized, Exploratory Trial.

Unlike praziquantel, artemisinin derivatives are effective against juvenile schistosome worms. We assessed the efficacy and safety of a single oral dose of artesunate plus sulfalene-pyrimethamine versus praziquantel in the treatment of Schistosoma mansoni. Seventy-three schoolchildren (aged 9-15 years) with confirmed S. mansoni infection in Rarieda, western Kenya, were randomly assigned to receive either a single oral dose of artesunate plus sulfalene-pyrimethamine (n = 39) or a single dose of praziquantel (n = 34). The cure and egg reduction rates at 4 weeks posttreatment were 69.4% (25/36) versus 80.6% (25/31) (P = 0.297) and 99.1% versus 97.5% (P = 0.607) in the artesunate plus sulfalene-pyrimethamine group versus praziquantel group, respectively. Fourteen children developed adverse events, and there were no serious adverse events. A single oral dose of artesunate plus sulfalene-pyrimethamine has efficacy comparable to that of praziquantel in the treatment of S. mansoni, but these results should be confirmed in larger randomized controlled trials.

Effects of structurally distinct human HDAC6 and HDAC6/HDAC8 inhibitors against S. mansoni larval and adult worm stages.

Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide caused by Platyhelminthes of the genus Schistosoma. The treatment of schistosomiasis relies on the long-term application of a single safe drug, praziquantel (PZQ). Unfortunately, PZQ is very effective on adult parasites and poorly on larval stage and immature juvenile worms; this can partially explain the re-infection in endemic areas where patients are likely to host parasites at different developmental stages concurrently. Moreover, the risk of development of drug resistance because of the widespread use of a single drug in a large population is nowadays a serious threat. Hence, research aimed at identifying novel drugs to be used alone or in combination with PZQ is needed. Schistosomes display morphologically distinct stages during their life cycle and epigenetic mechanisms are known to play important roles in parasite growth, survival, and development. Histone deacetylase (HDAC) enzymes, particularly HDAC8, are considered valuable for therapeutic intervention for the treatment of schistosomiasis. Herein, we report the phenotypic screening on both larvae and adult Schistosoma mansoni stages of structurally different HDAC inhibitors selected from the in-house Siena library. All molecules have previously shown inhibition profiles on human HDAC6 and/or HDAC8 enzymes. Among them we identified a quinolone-based HDAC inhibitor, NF2839, that impacts larval and adult parasites as well as egg viability and maturation in vitro. Importantly, this quinolone-based compound also increases histone and tubulin acetylation in S. mansoni parasites, thus representing a leading candidate for the development of new generation anti-Schistosoma chemotherapeutics.

Dietary glycemic and energy load differentially modulates Schistosoma mansoni-induced granulomatous inflammation and response to antiparasitic chemotherapy.

The impact of diet composition and energy content on schistosomiasis evolution and treatment efficacy is still controversial. This study compared the impact of sucrose-rich diet and intermittent fasting on Schistosoma mansoni infection and praziquantel (PZQ)-based chemotherapy response in mice. BALB/c mice were infected with S. mansoni and followed for 15 weeks. The animals were randomized into nine groups receiving high glycemic load (high-sucrose diet - HSD), low caloric load (standard chow alternate-day fasting - ADF), and standard chow ad libitum (AL). Eight weeks after S. mansoni infection, these groups remained untreated or were treated with PZQ (300 mg/kg/day) for 3 days. Our results indicated that parasite load (S. mansoni eggs and parasite DNA levels), granulomatous inflammation (granulomas number and size), and liver microstructural damage (reduction in hepatocytes number, increase in nucleus-cytoplasm ratio, connective stroma expansion and fibrosis) were increased in ADF-treated animals. These animals also showed decreased eggs retention, granulomatous inflammation and collagen accumulation in the small intestine. Conversely, HSD diet and PZQ treatment attenuated all these parameters and stimulated hepatic regenerative response. PZQ also stimulated fibrosis resolution in HSD-treated mice, effect that was limited ADF-exposed mice. Our findings indicate that dietary glycemic and energy load can modulate schistosomiasis progression and the severity of hepatic and intestinal granulomatous inflammation in untreated and PZQ-treated mice. Thus, lower intestinal eggs retention may potentially be linked to worsening liver disease in ADF, while attenuation of hepatic and intestinal granulomatous inflammation is consistent with reduced parasite load in HSD- and PZQ-treated animals.

A cross-sectional pilot household study of Schistosoma mansoni burden and associated morbidities in Lake Albert, Uganda.

OBJECTIVES: Schistosomiasis is persistent in Lake Albert, Uganda, but local data are limited. This study aims to describe the local burden of moderate-to-heavy infection and associated morbidity in all ages and identify factors associated with these outcomes to guide further research. METHODS: This cross-sectional pilot study was conducted in July-August, 2022 in four village sites (Walukuba, Rwentale, Kyabarangwa and Runga) of the Praziquantel in Preschoolers (PIP) trial. Residents (approximately four per household) of any age of households of PIP participants were eligible, but individuals <10 years were only enrolled if no older individuals were available. Socio-demographic information, household location, single stool Kato-Katz and hepatic ultrasound results were obtained for a convenience sampled subset of trial households. The primary outcome, moderate-to-heavy infection (≥100 eggs per gram of faeces), was analysed using mixed-effects logistic regression, with a household random effect. Univariate analyses were used for the secondary outcome, periportal fibrosis (Niamey protocol ultrasound image pattern C-F). RESULTS: Of 243 participants with a median age of 22 (interquartile range 12-33) years from 66 households, 49.8% (103/207 with a Kato-Katz result) had moderate-to-heavy infection and 11.2% (25/224 with ultrasound data) had periportal fibrosis. Moderate-to-heavy infection clustered by household (intraclass correlation coefficient = 0.11) and, in multivariable analysis, varied by village (Walukuba vs. Kyabarangwa adjusted odds ratio [aOR] 0.11, 95% CI 0.02-0.71), was highest in participants aged 10-15 years (vs. 5-9 years aOR 6.14, 95% CI 1.61-23.38) and lower in those reporting praziquantel treatment in the past year (aOR 0.39, 95% CI 0.18-0.88). CONCLUSIONS: In this setting, schistosome infection and morbidity are pervasive in all age groups. More intensive interventions are needed, for example more frequent praziquantel treatment, under investigation in the PIP trial and improved water and sanitation. More research is needed to understand local treatment barriers and optimal control strategies.

Development of prediction models to identify hotspots of schistosomiasis in endemic regions to guide mass drug administration.

Schistosomiasis is a neglected tropical disease affecting over 150 million people. Hotspots of Schistosoma transmission-communities where infection prevalence does not decline adequately with mass drug administration-present a key challenge in eliminating schistosomiasis. Current approaches to identify hotspots require evaluation 2-5 y after a baseline survey and subsequent mass drug administration. Here, we develop statistical models to predict hotspots at baseline prior to treatment comparing three common hotspot definitions, using epidemiologic, survey-based, and remote sensing data. In a reanalysis of randomized trials in 589 communities in five endemic countries, a regression model predicts whether Schistosoma mansoni infection prevalence will exceed the WHO threshold of 10% in year 5 ("prevalence hotspot") with 86% sensitivity, 74% specificity, and 93% negative predictive value (NPV; assuming 30% hotspot prevalence), and a regression model for Schistosoma haematobium achieves 90% sensitivity, 90% specificity, and 96% NPV. A random forest model predicts whether S. mansoni moderate and heavy infection prevalence will exceed a public health goal of 1% in year 5 ("intensity hotspot") with 92% sensitivity, 79% specificity, and 96% NPV, and a boosted trees model for S. haematobium achieves 77% sensitivity, 95% specificity, and 91% NPV. Baseline prevalence is a top predictor in all models. Prediction is less accurate in countries not represented in training data and for a third hotspot definition based on relative prevalence reduction over time ("persistent hotspot"). These models may be a tool to prioritize high-risk communities for more frequent surveillance or intervention against schistosomiasis, but prediction of hotspots remains a challenge.

A single locus determines praziquantel response in Schistosoma mansoni.

We previously performed a genome-wide association study (GWAS) to identify the genetic basis of praziquantel (PZQ) response in schistosomes, identifying two quantitative trait loci situated on chromosomes 2 and 3. We reanalyzed this GWAS using the latest (version 10) genome assembly showing that a single locus on chromosome 3, rather than two independent loci, determines drug response. These results reveal that PZQ response is monogenic and demonstrates the importance of high-quality genomic information.

Chronic intestinal schistosomiasis caused by co-infection with Schistosoma intercalatum and Schistosoma mansoni.

The Grand Round concerns a 24-year-old man from Zimbabwe who was studying and living in Poland. The patient had been complaining of abdominal pain, fatigue, alternating diarrhoea and constipation, and presence of blood in his stool for 3 years. The patient had the following diagnostic tests: colonoscopy, CT scan, histopathology, and parasitological and molecular tests. Results of the examinations showed that the cause of the patient's complaints was chronic intestinal schistosomiasis due to the co-infection with Schistosoma intercalatum and Schistosoma mansoni. The patient had two cycles of praziquantel therapy (Biltricide) and responded well to the treatment. In the Grand Round, we describe full diagnostics as well as clinical and therapeutic management in the patient with S intercalatum and S mansoni co-infection. This case allows us to draw attention to cases of forgotten chronic tropical diseases (including rare ones) in patients from regions with a high endemic index staying in non-endemic regions of the world for a long time. Co-infection with S intercalatum and S mansoni should be considered as a very rare clinical case.

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.

Baseline Liver Ultrasound Findings in Preschool Children From the Praziquantel in Preschoolers Trial in Lake Albert, Uganda.

BACKGROUND: Periportal fibrosis is a late-stage manifestation of chronic infection with Schistosoma mansoni . Praziquantel (PZQ), the only drug available for the treatment of schistosomiasis, has limited effect in treating established morbidity. Preschool-age children (PSAC) are not considered to be an at-risk population for severe morbidity. However, the prevalence of periportal fibrosis in PSAC in S. mansoni endemic settings is unknown. METHODS: As part of a phase II clinical trial comparing different dosing regimens of PZQ in children age 12-47 months infected with S. mansoni in Uganda ("praziquantel in preschoolers" trial), we present baseline results assessing liver ultrasound (US) findings as per the WHO Niamey Protocol. RESULTS: A total of 7/347 (2%) PSAC had Image Pattern C with pipe stems and echogenic rings suggestive of periportal fibrosis, 29/347 (8%) had Image Pattern B and 58 (17%) had evidence of periportal thickening There were higher adjusted odds of periportal thickening with older age [odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.07], primary maternal education (OR: 1.04; 95% CI: 1.00-1.07) and being taken to the lake weekly (OR: 3.02; 95% CI: 1.19-7.63). A further 44/347 children (13%) had a rounded caudal liver edge which was associated with high S. mansoni infection intensity (adjusted OR: 3.31; 95% CI: 1.46-7.51). CONCLUSIONS: Incipient schistosomiasis-related liver morbidity was detected in young children enrolled in the praziquantel in preschoolers trial. Adequate age-adjusted reference measurements for liver ultrasound findings in very small children are lacking but urgently needed. Schistosomiasis-related fibrosis may be delayed or averted with early and repeated PZQ treatment.

Auranofin attenuates Schistosoma mansoni egg-induced liver granuloma and fibrosis in mice.

Schistosomiasis is a serious tropical disease. Despite extensive research into the etiology of liver fibrosis, effective therapeutic options remain limited. This study aims to assess the effectiveness of auranofin in treating hepatic granuloma and fibrogenesis produced by Schistosoma (S.) mansoni eggs. Auranofin is a gold complex that contains thioglucose tetraacetate and triethylphosphine. Eighty BALB/c male mice were divided into four groups (n=20/group): negative control (GI), positive control (GII), and early (GIII) and late (GIV) treatment groups with oral auranofin according to beginning of treatment 4th week and 6th week post-infection. Mice were infected subcutaneously in a dose of 60±10 cercariae/mouse. Worm counts, egg loads, and oogram patterns were determined. Biochemical, histological, and immunostaining of interleukin-1ß (IL-1ß), Sirtuin 3 (SIRT3), and smooth muscle actin (SMA) were assessed. GIII showed a significant decrease in the total S. mansoni worm burden and ova/gram in liver tissue (with reduction percent of 63.07% and 78.26%, respectively). Schistosomal oogram patterns, immature and mature ova, also showed a significant decrease. The reduction in granuloma number and size was 40.63% and 48.66%, respectively, in GIII, whereas in GIV, the reduction percent was 76.63% and 67.08%. In addition, the degree of fibrosis was significantly diminished in both treated groups. GIV showed significant reduction in IL-1ß and SMA expression and increase in SIRT3 expression. These findings reveal how auranofin suppresses the development of liver fibrosis. Therefore, it is crucial to take another look at auranofin as a prospective medication for the treatment of S. mansoni egg-induced hepatic granuloma and consequent fibrosis.

Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development.

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.

Targeting the Schistosoma mansoni nutritional mechanisms to design new antischistosomal compounds.

The chemical classes of semicarbazones, thiosemicarbazones, and hydrazones are present in various compounds, each demonstrating diverse biological activities. Extensive studies have revealed their potential as schistosomicidal agents. Thiosemicarbazones, in particular, have shown inhibitory effects on Schistosoma mansoni's cathepsin B1 enzyme (SmCB1), which plays a crucial role in hemoglobin degradation within the worm's gut and its nutrition processes. Consequently, SmCB1 has emerged as a promising target for novel schistosomiasis therapies. Moreover, chloroquinoline exhibits characteristics in its aromatic structure that hold promise for developing SmCB1 inhibitors, along with its interaction with hemoglobin's heme group, potentially synergizing against the parasite's gut. In this context, we report the synthesis of 22 hybrid analogs combining hydrazones and quinolines, evaluated against S. mansoni. Five of these hybrids demonstrated schistosomicidal activity in vitro, with GPQF-8Q10 being the most effective, causing worm mortality within 24 h at a concentration of 25 µM. GPQF-8Q8 proved to be the most promising in vivo, significantly reducing egg presence in feces (by 52.8%) and immature eggs in intestines (by 45.8%). These compounds exhibited low cytotoxicity in Vero cells and an in in vivo animal model (Caenorhabditis elegans), indicating a favorable selectivity index. This suggests their potential for the development of new schistosomiasis therapies. Further studies are needed to uncover specific target mechanisms, but these findings offer a promising starting point.

Transcriptome analysis of peripheral blood of Schistosoma mansoni infected children from the Albert Nile region in Uganda reveals genes implicated in fibrosis pathology.

Over 290 million people are infected by schistosomes worldwide. Schistosomiasis control efforts focus on mass drug treatment with praziquantel (PZQ), a drug that kills the adult worm of all Schistosoma species. Nonetheless, re-infections have continued to be detected in endemic areas with individuals living in the same area presenting with varying infection intensities. Our objective was to characterize the transcriptome profiles in peripheral blood of children between 10-15 years with varying intensities of Schistosoma mansoni infection living along the Albert Nile in Uganda. RNA extracted from peripheral blood collected from 44 S. mansoni infected (34 high and 10 low by circulating anodic antigen [CAA] level) and 20 uninfected children was sequenced using Illumina NovaSeq S4 and the reads aligned to the GRCh38 human genome. Differential gene expression analysis was done using DESeq2. Principal component analysis revealed clustering of gene expression by gender when S. mansoni infected children were compared with uninfected children. In addition, we identified 14 DEGs between S. mansoni infected and uninfected individuals, 56 DEGs between children with high infection intensity and uninfected individuals, 33 DEGs between those with high infection intensity and low infection intensity and no DEGs between those with low infection and uninfected individuals. We also observed upregulation and downregulation of some DEGs that are associated with fibrosis and its regulation. These data suggest expression of fibrosis associated genes as well as genes that regulate fibrosis in S. mansoni infection. The relatively few significant DEGS observed in children with schistosomiasis suggests that chronic S. mansoni infection is a stealth infection that does not stimulate a strong immune response.