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1.  Effect of Maternal Schistosoma mansoni Infection and Praziquantel Treatment During Pregnancy on Schistosoma mansoni Infection and Immune Responsiveness among Offspring at Age Five Years 
Introduction
Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years.
Methods
In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years.
Results
Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not.
Conclusion
We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease.
Author Summary
Infections with the blood fluke Schistosoma mansoni that cause schistosomiasis (also called Bilharzia) were not usually treated during pregnancy until 2002, but in 2002 a World Health Organization (WHO) team of experts recommended that praziquantel treatment of S. mansoni during pregnancy should be done. However, there was limited information on the effects of maternal S. mansoni infection and treatment during pregnancy on the outcomes in the offspring. We conducted a study in the Entebbe peninsula within Lake Victoria in Uganda to examine whether maternal S. mansoni infection or its treatment during pregnancy may have effects on the children's susceptibility to the infection. The children were examined at age five years old for the level of S. mansoni infection and for immune responses to schistosomes. At five years old few of the children in our study cohort were infected with S. mansoni. Our findings suggest that maternal infection with, or praziquantel treatment of S. mansoni during pregnancy did not influence the level of S. mansoni infection among the offspring. However our findings suggest an influence on regulation of the body's immune responses to schistosomes, which may have some effect on the progress of disease manifestations. This is an issue that needs further investigation.
doi:10.1371/journal.pntd.0002501
PMCID: PMC3798616  PMID: 24147175
2.  Impact of Schistosoma mansoni on Malaria Transmission in Sub-Saharan Africa 
Background
Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children.
Methodology
We developed a co-epidemic model of malaria and S. mansoni transmission dynamics which takes into account key epidemiological interaction between the two diseases in terms of elevated malaria incidence among individuals with S. mansoni high egg output. The model was parameterized for S. mansoni high-risk endemic communities, using epidemiological and clinical data of the interaction between S. mansoni and malaria among children in sub-Saharan Africa. We evaluated the potential impact of the S. mansoni–malaria interaction and mass treatment of schistosomiasis on malaria prevalence in co-endemic communities.
Principal Findings
Our results suggest that in the absence of mass drug administration of praziquantel, the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission, in S. mansoni high-risk endemic communities. However, when malaria treatment is used in combination with praziquantel, mass praziquantel administration may increase the effectiveness of malaria control intervention strategy for reducing malaria prevalence in malaria- S. mansoni co-endemic communities.
Conclusions/Significance
Schistosomiasis treatment and control programmes in regions where S. mansoni and malaria are highly prevalent may have indirect benefits on reducing malaria transmission as a result of disease interactions. In particular, mass praziquantel administration may not only have the direct benefit of reducing schistosomiasis infection, it may also reduce malaria transmission and disease burden.
Author Summary
Malaria and Schistosoma mansoni are co-endemic in many regions of sub-Saharan Africa. Evidence from clinical and epidemiological studies support the hypothesis that concurrent infection with S. mansoni is associated with greater malaria incidence among school-age children. We use mathematical modeling to evaluate the epidemiological impact of S. mansoni infection on malaria transmission in sub-Saharan Africa. Using epidemiological data on the increased risk of malaria incidence in S. mansoni endemic communities from Senegal, we developed a co-epidemic model of malaria and S. mansoni transmission dynamics to address key epidemiological interactions between the two diseases. Parameterizing our model for S. mansoni high-risk endemic communities, we show that the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission. Moreover, we show that in addition to reducing schistosomiasis health burden, mass praziquantel administration will generate indirect benefit in terms of reducing malaria transmission and disease burden in S. mansoni–malaria co-endemic communities. Our findings indicate the possible benefit of scaling up schistosomiasis control efforts in sub-Saharan Africa, and especially in areas were S. mansoni and malaria are highly prevalent.
doi:10.1371/journal.pntd.0003234
PMCID: PMC4199517  PMID: 25329403
3.  Schistosome Syntenin Partially Protects Vaccinated Mice against Schistosoma mansoni Infection 
Background
Schistosomiasis is a neglected tropical disease caused by several species of trematode of the genus Schistosoma. The disease affects more than 200 million people in the world and causes up to 280,000 deaths per year, besides having high morbidity due to chronic illness that damages internal organs. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control disease is a combination of drug treatment and immunization with an anti-schistosome vaccine. Among the most promising molecules as vaccine candidates are the proteins present in the tegument and digestive tract of the parasite.
Methodology/Principal Findings
In this study, we describe for the first time Schistosoma mansoni syntenin (SmSynt) and we evaluate its potential as a recombinant vaccine. We demonstrate by real-time PCR that syntenin is mainly expressed in intravascular life stages (schistosomula and adult worms) of the parasite life cycle and, by confocal microscopy, we localize it in digestive epithelia in adult worms and schistosomula. Administration of siRNAs targeting SmSynt leads to the knock-down of syntenin gene and protein levels, but this has no demonstrable impact on parasite morphology or viability, suggesting that high SmSynt gene expression is not essential for the parasites in vitro. Mice immunization with rSmSynt, formulated with Freund's adjuvant, induces a Th1-type response, as suggested by the production of IFN-γ and TNF-α by rSmSynt-stimulated cultured splenocytes. The protective effect conferred by vaccination with rSmSynt was demonstrated by 30–37% reduction of worm burden, 38–43% reduction in the number, and 35–37% reduction in the area, of liver granulomas.
Conclusions/Significance
Our report is the first characterization of syntenin in Schistosoma mansoni and our data suggest that this protein is a potential candidate for the development of a multi-antigen vaccine to control schistosomiasis.
Author Summary
Schistosomiasis affects more than 200 million people worldwide and causes up to 280,000 deaths per year. In terms of global mortality and morbidity, this disease is the most important human helminth infection. Current control strategies are based on chemotherapy, but recurrent re-infection of people living in endemic areas makes many researchers, and also the World Health Organization, search for an effective vaccine to provide protection against schistosomiasis. Substantial efforts have been committed to the characterization of new antigens for an anti-schistosome vaccine and, in order to find new targets for vaccine and/or drug development, we searched transcriptomics and proteomics of Schistosoma mansoni and identified the protein syntenin (SmSynt) for analysis. In this study, we characterize SmSynt and evaluate its potential as a vaccine candidate to protect mice against S. mansoni infection. We demonstrate that SmSynt is expressed in schistosomula and adult worms, the intravascular stages of S. mansoni and it is located in the intestinal tract of the worms, an important host/parasite interface. Furthermore, vaccination of mice with rSmSynt confers partial protection against S. mansoni challenge infection and ameliorates parasite-induced liver pathology. Our data suggest that SmSynt is a potential candidate in the development of a vaccine against schistosomiasis.
doi:10.1371/journal.pntd.0003107
PMCID: PMC4140676  PMID: 25144756
4.  Effectiveness of a Pre-treatment Snack on the Uptake of Mass Treatment for Schistosomiasis in Uganda: A Cluster Randomized Trial 
PLoS Medicine  2014;11(5):e1001640.
In a cluster randomized trial, Simon Muhumuza and colleagues examine the effectiveness of a pre-treament snack given to school-aged children on the uptake of mass treatment for schistosomiasis in Uganda.
Please see later in the article for the Editors' Summary
Background
School-based mass treatment with praziquantel is the cornerstone for schistosomiasis control in school-aged children. However, uptake of treatment among school-age children in Uganda is low in some areas. The objective of the study was to examine the effectiveness of a pre-treatment snack on uptake of mass treatment.
Methods and Findings
In a cluster randomized trial carried out in Jinja district, Uganda, 12 primary schools were randomized into two groups; one received education messages for schistosomiasis prevention for two months prior to mass treatment, while the other, in addition to the education messages, received a pre-treatment snack shortly before mass treatment. Four weeks after mass treatment, uptake of praziquantel was assessed among a random sample of 595 children in the snack schools and 689 children in the non-snack schools as the primary outcome. The occurrence of side effects and the prevalence and mean intensity of Schistosoma mansoni infection were determined as the secondary outcomes. Uptake of praziquantel was higher in the snack schools, 93.9% (95% CI 91.7%–95.7%), compared to that in the non-snack schools, 78.7% (95% CI 75.4%–81.7%) (p = 0.002). The occurrence of side effects was lower in the snack schools, 34.4% (95% CI 31.5%–39.8%), compared to that in the non-snack schools, 46.9% (95% CI 42.2%–50.7%) (p = 0.041). Prevalence and mean intensity of S. mansoni infection was lower in the snack schools, 1.3% (95% CI 0.6%–2.6%) and 38.3 eggs per gram of stool (epg) (95% CI 21.8–67.2), compared to that in the non-snack schools, 14.1% (95% CI 11.6%–16.9%) (p = 0.001) and 78.4 epg (95% CI 60.6–101.5) (p = 0.001), respectively.
Conclusions
Our results suggest that provision of a pre-treatment snack combined with education messages achieves a higher uptake compared to the education messages alone. The use a pre-treatment snack was associated with reduced side effects as well as decreased prevalence and intensity of S. mansoni infection.
Trial registration
www.ClinicalTrials.gov NCT01869465
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 240 million people are infected with schistosomes, a parasitic worm found in tropical and sub-tropical fresh water. Schistosomes reproduce in snails, which release free-swimming infectious parasites that burrow into the skin of people when they wash or swim in contaminated water. Once inside a person, the parasites turn into larvae and migrate to the liver, where they become juvenile worms. These mature into 10–20 mm long adult worms and take up residence in the veins draining the gut or bladder where they mate and release eggs, some of which pass into the feces and go back into water where they hatch and infect fresh snails. Most people have no symptoms when they are first infected with schistosomes but some develop a rash or itchy skin. Later symptoms include fever, chills, cough, and muscle aches. Without treatment, schistosomiasis can persist for years, eventually causing liver, gut, bladder, and spleen damage. In Africa alone, schistosomiasis kills about 280,000 people annually.
Why Was This Study Done?
Strategies for the control of schistosomiasis include the provision of clean water and adequate sanitation, and education. However, the cornerstone of control is the reduction of disease through periodic, targeted treatment with the anti-schistosomal drug praziquantel. One group that is targeted for treatment in countries affected by schistosomiasis is school-aged children. For this approach to be successful, experts recommend regular treatment of at least 75% of school-age children at risk of infection. Unfortunately, the uptake of the intervention is often low, partly because children fear praziquantel's side effects, which include diarrhea, and vomiting. The risk of developing side effects can be reduced by eating food just before taking the drug. In this cluster randomized trial (a study that compares outcomes in groups of people randomly assigned to receive different treatments), the researchers investigate whether the provision of a pre-treatment snack improves the uptake of praziquantel among school children in Jinja district of Uganda, a country that has adopted school-based mass drug administration as part of its national schistosomiasis control program. The researchers also investigated whether this intervention reduces the occurrence of side effects attributable to praziquantel, the prevalence of schistosomiasis (the proportion of the population that is infected), and the infection intensity (indicated by the density of eggs in stool).
What Did the Researchers Do and Find?
The researchers randomly assigned 12 primary schools to receive education messages for 2 months before mass treatment with praziquantel or the same education messages plus a mango juice and donut snack just before treatment. The education messages included information about the dangers of schistosome infection, the importance of preventative treatment with praziquantel, and information about taking the drug with food to avoid side effects. Four weeks after mass treatment, praziquantel uptake was assessed by self report in 595 children chosen randomly from the snack schools and 689 children from the no-snack schools. Uptake of praziquantel in the snack and no-snack schools was 93.9% and 78.7%, respectively, a significant difference in outcomes that is unlikely to be a chance event. The occurrence of self-reported side effects, the prevalence of schistosome infection, and the average intensity of infection were all significantly lower in the snack schools than in the no-snack schools.
What Do These Findings Mean?
These findings suggest that the provision of a pre-treatment snack combined with education messages improved uptake of mass treatment for schistosomiasis among school children in Uganda compared to education messages alone. The intervention also reduced the occurrence of side effects, the prevalence of infection, and the infection intensity. Because uptake and the occurrence of side effects were determined by self-report, some children may have provided socially desirable answers. That is, they may have said they took the drug when they didn't because they knew that is what the researchers wanted to hear. However, the infection prevalence and intensity findings validate the self-reported uptake. The researchers conclude that the provision of a snack to mitigate the side effects of praziquantel could have motivated the children to take the treatment. If future trials show that the intervention is cost-effective, the researchers suggest that the provision of pre-treatment food should be integrated into school-based mass treatment programs for schistosomiasis control at the national level in Uganda and in similar settings elsewhere in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001640.
The World Health Organization provides detailed information about schistosomiasis (in several languages)
The US Centers for Disease Control and Prevention provides information for the public and for health professionals about all aspects of schistosomiasis (in English and Spanish)
The UK National Health Service Choices website also provides information about schistosomiasis
More information about the Evaluation of Strategies for Improved Uptake of Preventive Treatment for Intestinal Schistosomiasis trial is available
The End Fund, a US not-for-profit organization that aims to tackle schistosomiasis and other neglected tropical diseases, has a personal story about dealing with schistosomiasis
doi:10.1371/journal.pmed.1001640
PMCID: PMC4019501  PMID: 24824051
5.  A Loop-Mediated Isothermal Amplification (LAMP) Assay for Early Detection of Schistosoma mansoni in Stool Samples: A Diagnostic Approach in a Murine Model 
Background
Human schistosomiasis, mainly due to Schistosoma mansoni species, is one of the most prevalent parasitic diseases worldwide. To overcome the drawbacks of classical parasitological and serological methods in detecting S. mansoni infections, especially in acute stage of the disease, development of cost-effective, simple and rapid molecular methods is still needed for the diagnosis of schistosomiasis. A promising approach is the loop-mediated isothermal amplification (LAMP) technology. Compared to PCR-based assays, LAMP has the advantages of reaction simplicity, rapidity, specificity, cost-effectiveness and higher amplification efficiency. Additionally, as results can be inspected by the naked eye, the technique has great potential for use in low-income countries.
Methodology/Principal findings
A sequence corresponding to a mitochondrial S. mansoni minisatellite DNA region was selected as a target for designing a LAMP-based method to detect S. mansoni DNA in stool samples. We used a S. mansoni murine model to obtain well defined stool and sera samples from infected mice with S. mansoni cercariae. Samples were taken weekly from week 0 to 8 post-infection and the Kato-Katz and ELISA techniques were used for monitoring the infection. Primer set designed were tested using a commercial reaction mixture for LAMP assay and an in house mixture to compare results. Specificity of LAMP was tested using 16 DNA samples from different parasites, including several Schistosoma species, and no cross-reactions were found. The detection limit of our LAMP assay (SmMIT-LAMP) was 1 fg of S. mansoni DNA. When testing stool samples from infected mice the SmMIT-LAMP detected S. mansoni DNA as soon as 1 week post-infection.
Conclusions/Significance
We have developed, for the first time, a cost-effective, easy to perform, specific and sensitive LAMP assay for early detection of S. mansoni in stool samples. The method is potentially and readily adaptable for field diagnosis and disease surveillance in schistosomiasis-endemic areas.
Author Summary
Schistosomiasis is one of the most widespread of all human parasitic diseases, Schistosoma mansoni being the most important species causing human intestinal schistosomiasis. The diagnosis of the disease is mainly based on parasitological and serological methods, but they are not effective in detecting S. mansoni infections in the acute stage of the disease. New diagnostic tools to detect the disease during the first weeks would be desirable, permitting early treatment and preventing the pathology associated with chronic infections. An approach is the loop-mediated isothermal amplification (LAMP) technique, which can amplify DNA with high specificity and sensitivity under isothermal conditions. DNA amplification and reading of results require minimum equipment, thus the technique has great potential for use in diagnosis of neglected tropical diseases. In our study, we developed and evaluated a LAMP assay for the early detection of S. mansoni DNA in stool samples from mice experimentally infected with the parasite. The results indicated that our LAMP assay is specific, sensitive and cost-effective in detecting S. mansoni DNA in stool samples as soon as one week post-infection, when parasitological and serological methods are not effective. The assay has the potential to be developed further as a field diagnostic tool for use in schistosomiasis-endemic areas.
doi:10.1371/journal.pntd.0003126
PMCID: PMC4154662  PMID: 25187956
6.  Sensitivity and Specificity of Multiple Kato-Katz Thick Smears and a Circulating Cathodic Antigen Test for Schistosoma mansoni Diagnosis Pre- and Post-repeated-Praziquantel Treatment 
Background
Two Kato-Katz thick smears (Kato-Katzs) from a single stool are currently recommended for diagnosing Schistosoma mansoni infections to map areas for intervention. This ‘gold standard’ has low sensitivity at low infection intensities. The urine point-of-care circulating cathodic antigen test (POC-CCA) is potentially more sensitive but how accurately they detect S. mansoni after repeated praziquantel treatments, their suitability for measuring drug efficacy and their correlation with egg counts remain to be fully understood. We compared the accuracies of one to six Kato-Katzs and one POC-CCA for the diagnosis of S. mansoni in primary-school children who have received zero to ten praziquantel treatments. We determined the impact each diagnostic approach may have on monitoring and evaluation (M&E) and drug-efficacy findings.
Method/Principle Findings
In a high S. mansoni endemic area of Uganda, three days of consecutive stool samples were collected from primary school-aged children (six - 12 years) at five time-points in year one: baseline, one-week-post-, four-weeks-post-, six-months-post-, and six-months-one-week-post-praziquantel and three time-points in years two and three: pre-, one-week-post- and four-weeks-post-praziquantel-treatment/retreatment (n = 1065). Two Kato-Katzs were performed on each stool. In parallel, one urine sample was collected and a single POC-CCA evaluated per child at each time-point in year one (n = 367). At baseline, diagnosis by two Kato-Katzs (sensitivity = 98.6%) or one POC-CCA (sensitivity = 91.7%, specificity = 75.0%) accurately predicted S. mansoni infections. However, one year later, a minimum of three Kato-Katzs, and two years later, five Kato-Katzs were required for accurate diagnosis (sensitivity >90%) and drug-efficacy evaluation. The POC-CCA was as sensitive as six Kato-Katzs four-weeks-post and six-months-post-treatment, if trace readings were classified as positive.
Conclusions/Significance
Six Kato-Katzs (two/stool from three stools) and/or one POC-CCA are required for M&E or drug-efficacy studies. Although unable to measure egg reduction rates, one POC-CCA appears to be more sensitive than six Kato-Katzs at four-weeks-post-praziquantel (drug efficacy) and six-months-post-praziquantel (M&E).
Author Summary
Schistosomiasis is a parasitic disease infecting over 200 million people. It remains a major public health concern despite treatment of over 120 million people in sub-Saharan Africa alone. Accurate diagnostic methods are essential for monitoring drug efficacy and long-term control program success. The World Health Organization recommends two Kato-Katz thick smears (Kato-Katzs) from a single stool for Schistosoma mansoni diagnosis to map prevalence and areas for control interventions. Although highly specific, Kato-Katzs are thought to be insensitive at low egg counts. The recently refined urine point-of-care circulating cathodic antigen test (POC-CCA) has been proposed as a diagnostic alternative for mapping areas for interventions, and potentially for assessing drug efficacy. Over three years we assessed the accuracy of six Kato-Katzs and a single POC-CCA in detecting infections in Ugandan primary-school children at 11 time points with repeated praziquantel treatments. Our results demonstrate that two Kato-Katzs accurately detect S. mansoni infection pre-treatment, but at least three days of two Kato-Katzs per stool or one POC-CCA are required for annual monitoring and treatment evaluation and/or drug-efficacy studies. One POC-CCA may be more sensitive in measuring S. mansoni prevalence than six Kato-Katzs, but its accuracies for rigorous intensity measures are still to be proven.
doi:10.1371/journal.pntd.0003139
PMCID: PMC4161328  PMID: 25211217
7.  Schistosomiasis Mansoni: Novel Chemotherapy Using a Cysteine Protease Inhibitor 
PLoS Medicine  2007;4(1):e14.
Background
Schistosomiasis is a chronic, debilitating parasitic disease infecting more than 200 million people and is second only to malaria in terms of public health importance. Due to the lack of a vaccine, patient therapy is heavily reliant on chemotherapy with praziquantel as the World Health Organization–recommended drug, but concerns over drug resistance encourage the search for new drug leads.
Methods and Findings
The efficacy of the vinyl sulfone cysteine protease inhibitor K11777 was tested in the murine model of schistosomiasis mansoni. Disease parameters measured were worm and egg burdens, and organ pathology including hepato- and splenomegaly, presence of parasite egg–induced granulomas in the liver, and levels of circulating alanine aminotransferase activity as a marker of hepatocellular function. K11777 (25 mg/kg twice daily [BID]), administered intraperitoneally at the time of parasite migration through the skin and lungs (days 1–14 postinfection [p.i.]), resulted in parasitologic cure (elimination of parasite eggs) in five of seven cases and a resolution of other disease parameters. K11777 (50 mg/kg BID), administered at the commencement of egg-laying by mature parasites (days 30–37 p.i.), reduced worm and egg burdens, and ameliorated organ pathology. Using protease class-specific substrates and active-site labeling, one molecular target of K11777 was identified as the gut-associated cathepsin B1 cysteine protease, although other cysteine protease targets are not excluded. In rodents, dogs, and primates, K11777 is nonmutagenic with satisfactory safety and pharmacokinetic profiles.
Conclusions
The significant reduction in parasite burden and pathology by this vinyl sulfone cysteine protease inhibitor validates schistosome cysteine proteases as drug targets and offers the potential of a new direction for chemotherapy of human schistosomiasis.
A significant reduction in parasite burden and pathology by a vinyl sulfone cysteine protease inhibitor suggests a new direction for chemotherapy of human schistosomiasis.
Editors' Summary
Background.
Schistosomiasis, a disease caused by a type of parasitic flatworm that lives in the blood, infects around 200 million people worldwide. The disease is a serious problem in sub-Saharan Africa, South America, China, and southeast Asia. Although this disease can kill, it is better known as a lifelong chronic infection with debilitating symptoms mainly due to an immune reaction raised against parasite eggs trapped in the liver, spleen, and gut. The worm's life cycle is complicated and involves a free-swimming form that emerges from certain types of snails that live in lakes and ponds. This can penetrate the skin of people in contact with the water. After a period spent in the skin and around the lungs, the parasites move to veins around the gut, and develop into adult worms that mate and lay eggs. These eggs eventually return to the water through the person's feces or urine. A particular group of proteins called cysteine proteases are thought to be very important in the biology of these worms, especially in their function as digestive enzymes in the parasite's gut. These proteases could represent an exciting opportunity for development of new drugs to treat schistosomiasis. The researchers are looking at whether it is possible to block the activity of cysteine proteases and, as a result, kill the worms or prevent them from developing and thriving.
Why Was This Study Done?
At the moment there is only one drug, praziquantel, in common use for treatment of schistosomiasis; it is cheap and effective. However many organizations are worried about relying on a single drug to treat a serious disease which affects so many people worldwide. The research group here has been looking at molecules that block cysteine protease activity, to see if any of these could be good drug candidates for schistosomiasis. One molecule they have been looking at goes by the name of K11777, which is under evaluation as a drug candidate for another parasitic infection (Chagas' disease). Here, the researchers wanted to find out whether K11777 had any activity against schistosome worms.
What Did the Researchers Do and Find?
In this study, the researchers deliberately infected laboratory mice with the schistosome parasite. These mice were then either injected with K11777 solution twice daily, or with equivalent volumes of water as a comparison. The researchers examined the effects of injecting K11777 either “early” in infection (using a 14 day course, starting 1 day after infection with the parasite) or “late” in the worms' development (using an 8 day treatment course starting 30 days after infection). The outcomes used as measures of success of treatment with K11777 included the number of worms recovered from mice after euthanasia, the number of worm eggs counted in the liver; the extent of the damage to the liver; and finally, the researchers also looked at activity levels of cysteine proteases in the worms themselves, in particular, those proteases associated with the parasite gut.
The results of the early-treatment experiment showed a substantial decrease in worm numbers and egg production. In five of the seven mice treated, eggs were eliminated entirely. Also, there was little measurable liver damage. For the late-treatment experiment, decreased burdens of worms and eggs in the livers of K11777 treated mice were also found, and there was less damage to the livers. Those worms surviving treatment and removed from mice also had much less activity of gut cysteine proteases suggesting that K11777 exerts its effects by targeting worm cysteine proteases.
What Do These Findings Mean?
These experiments show that K11777 is a potent antischistosomal agent in mice. It might therefore be a good ‘candidate' molecule for developing future treatments for human schistosomiasis. However, before that stage can be reached, it would be important to carry out clinical trials to test whether K11777 is both safe and effective in schistosomiasis patients. Full details as to which worm cysteine protease(s) is the critical target of K11777 would also need to be worked out, and more information would be needed as to whether the dosing plan used in this study (twice-daily injections for a week to 14 days) can be decreased.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040014.
World Health Organization pages about schistosomiasis including links to details on further research into the disease
Information from the US Centers for Disease Control for patients and health professionals about schistosomiasis
Wikipedia pages on schistosomiasis (Wikipedia is an internet encyclopedia anyone can edit)
PLoS Neglected Tropical Diseases is a new journal from the Public Library of Science that is devoted to publishing research on the world's most neglected tropical diseases, including schistosomiasis
doi:10.1371/journal.pmed.0040014
PMCID: PMC1764436  PMID: 17214506
8.  Influence of Exposure History on the Immunology and Development of Resistance to Human Schistosomiasis Mansoni 
Background
Previous studies suggest that humans can acquire immunity to reinfection with schistosomes, most probably due to immunologic mechanisms acquired after exposure to dying schistosome worms.
Methodology/Principal Findings
We followed longitudinally two cohorts of adult males occupationally exposed to Schistosoma mansoni by washing cars (120 men) or harvesting sand (53 men) in Lake Victoria. Men were treated with praziquantel each time S. mansoni infection was detected. In car washers, a significant increase in resistance to reinfection, as measured by the number of cars washed between cure and reinfection, was observed after the car washers had experienced, on average, seven cures. In the car washers who developed resistance, the level of schistosome-specific IgE increased between baseline and the time at which development of resistance was first evidenced. In the sand harvesters, a significant increase in resistance, as measured by the number of days worked in the lake between cure and reinfection, was observed after only two cures. History of exposure to S. mansoni differed between the two cohorts, with the majority of sand harvesters being lifelong residents of a village endemic for S. mansoni and the majority of car washers having little exposure to the lake before they began washing cars. Immune responses at study entry were indicative of more recent infections in car washers and more chronic infections in sand harvesters.
Conclusions/Significance
Resistance to reinfection with S. mansoni can be acquired or augmented by adults after multiple rounds of reinfection and cure, but the rate at which resistance is acquired by this means depends on immunologic status and history of exposure to S. mansoni infection.
Author Summary
Schistosomiasis is a parasitic blood fluke infection of 200 million people worldwide. We have shown that humans can acquire immunity to reinfection after repeated exposures and cures with the drug praziquantel. The increase in resistance to reinfection was associated with an increase in schistosome-specific IgE. The ability to develop resistance and the rate at which resistance was acquired varied greatly in two cohorts of men within close geographic proximity and with similar occupational exposures to schistosomes. These differences are likely attributable to differences in history of exposure to Schistosoma mansoni infection and immunologic status at baseline, with those acquiring immunity faster having lifelong S. mansoni exposure and immunologic evidence of chronic S. mansoni infection. As many conflicting results have been reported in the literature regarding immunologic parameters associated with the development of resistance to schistosome infection, exposure history and prior immune status should be considered in the design of future immuno-epidemiologic studies.
doi:10.1371/journal.pntd.0000637
PMCID: PMC2843635  PMID: 20351784
9.  Bladder Morbidity and Hepatic Fibrosis in Mixed Schistosoma haematobium and S. mansoni Infections: A Population-Wide Study in Northern Senegal 
Background
The global distribution map of schistosomiasis shows a large overlap of Schistosoma haematobium- and S. mansoni-endemic areas in Africa. Yet, little is known about the consequences of mixed Schistosoma infections for the human host. A recent study in two neighboring co-endemic communities in Senegal indicated that infection intensities of both species were higher in mixed than in single infections. Here, we investigated the relationship between mixed Schistosoma infections and morbidity in the same population. So far, this has only been studied in children.
Methods
Schistosoma infection was assessed by microscopy. Schistosoma-specific morbidity was assessed by ultrasound according to WHO guidelines. Multivariable logistic regression models were used to identify independent risk factors for morbidity.
Principal Findings
Complete parasitological and morbidity data were obtained from 403 individuals. Schistosoma haematobium-specific bladder morbidity was observed in 83% and S. mansoni-specific hepatic fibrosis in 27% of the participants. Bladder morbidity was positively associated with S. haematobium infection intensity (OR = 1.9 (95% CI 1.3–2.9) for a 10-fold increase in intensity). Moreover, people with mixed infections tended to have less bladder morbidity than those with single S. haematobium infections (OR = 0.3 (95% CI 0.1–1.1)). This effect appeared to be related to ectopic S. mansoni egg elimination in urine. Hepatic fibrosis on the other hand was not related to S. mansoni infection intensity (OR = 0.9 (95% CI 0.6–1.3)), nor to mixed infections (OR = 1.0 (95% CI 0.7–1.7)).
Conclusions/Significance
This is the first population-wide study on the relationship between mixed Schistosoma infections and morbidity. Mixed infections did not increase the risk of S. mansoni-associated morbidity. They even tended to reduce the risk of S. haematobium-associated morbidity, suggesting a protective effect of S. mansoni infection on bladder morbidity. These unexpected results may have important consequences for schistosomiasis control in co-endemic areas and warrant further investigation.
Author Summary
In the developing world, over 207 million people are infected with parasitic Schistosoma worms. Schistosoma haematobium and S. mansoni are the most abundant species in Africa and many people carry both. Yet, little is known about the consequences of such mixed infections. In general, S. haematobium affects the urinary tract of the host and S. mansoni the liver. Here, we investigated the effect of mixed Schistosoma infection on these health problems. We examined 403 people from northern Senegal for Schistosoma infections as well as for abnormalities of the urinary bladder and liver. Recently, we observed that people with mixed Schistosoma infections had generally higher infection intensities than those with single infections. The present study showed that abnormalities of the urinary bladder were more common in heavy than in light S. haematobium infections. Also, they were more common in single S. haematobium than in mixed infections. So far, only two studies have looked into the relationship between mixed Schistosoma infection and abnormalities of the bladder and liver, but only investigated children. Our findings suggest a possible protective effect of S. mansoni on bladder disease, in children as well as in adults. This may have important consequences for schistosomiasis control in co-endemic areas.
doi:10.1371/journal.pntd.0001829
PMCID: PMC3459828  PMID: 23029589
10.  Mefloquine—An Aminoalcohol with Promising Antischistosomal Properties in Mice 
Background
The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the antimalarial drug mefloquine possesses promising antischistosomal properties in mice.
Methodology/Principal Findings
A single dose of mefloquine (200 or 400 mg/kg) administered orally to mice infected with adult Schistosoma mansoni or adult S. japonicum resulted in high or complete total and female worm burden reductions (72.3%–100%). Importantly, high worm burden reductions were also observed for young developing stages of S. mansoni and S. japonicum harbored in the mouse. Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection.
Conclusions/Significance
Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality. Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes. It will be interesting to investigate whether mefloquine, which is widely and effectively used for the treatment of malaria, has an impact on schistosomiasis in areas where both malaria and schistosomiasis co-exist.
Author Summary
Schistosomiasis is a chronic and debilitating disease that occurs in tropical and subtropical areas. The disease is caused by an infection with a parasitic worm and affects over 200 million people. The treatment and control of schistosomiasis relies on a single drug, praziquantel. This drug is increasingly used, and hence there is mounting concern about the development of resistance to praziquantel. Here we report that mefloquine, a marketed drug for prophylaxis and treatment of malaria, shows promising antischistosomal properties in laboratory studies with mice. When mefloquine was orally administered at a single dose of 200 or 400 mg/kg to mice infected with young or adult stages of the parasitic worm Schistosoma mansoni or S. japonicum, we found very high worm burden reductions. We also found high worm burden reductions when mefloquine enantiomers were given to mice infected with adult S. mansoni. Further studies are needed because our results might be of public health relevance. Indeed, mefloquine is widely used for prophylaxis and treatment of malaria, often in areas where both malaria and schistosomiasis co-exist. In such areas, it might be possible that the use of mefloquine against malaria reduces the burden of schistosomiasis.
doi:10.1371/journal.pntd.0000350
PMCID: PMC2600813  PMID: 19125172
11.  Bayesian Risk Mapping and Model-Based Estimation of Schistosoma haematobium–Schistosoma mansoni Co-distribution in Côte d′Ivoire 
Background
Schistosoma haematobium and Schistosoma mansoni are blood flukes that cause urogenital and intestinal schistosomiasis, respectively. In Côte d′Ivoire, both species are endemic and control efforts are being scaled up. Accurate knowledge of the geographical distribution, including delineation of high-risk areas, is a central feature for spatial targeting of interventions. Thus far, model-based predictive risk mapping of schistosomiasis has relied on historical data of separate parasite species.
Methodology
We analyzed data pertaining to Schistosoma infection among school-aged children obtained from a national, cross-sectional survey conducted between November 2011 and February 2012. More than 5,000 children in 92 schools across Côte d′Ivoire participated. Bayesian geostatistical multinomial models were developed to assess infection risk, including S. haematobium–S. mansoni co-infection. The predicted risk of schistosomiasis was utilized to estimate the number of children that need preventive chemotherapy with praziquantel according to World Health Organization guidelines.
Principal Findings
We estimated that 8.9% of school-aged children in Côte d′Ivoire are affected by schistosomiasis; 5.3% with S. haematobium and 3.8% with S. mansoni. Approximately 2 million annualized praziquantel treatments would be required for preventive chemotherapy at health districts level. The distinct spatial patterns of S. haematobium and S. mansoni imply that co-infection is of little importance across the country.
Conclusions/Significance
We provide a comprehensive analysis of the spatial distribution of schistosomiasis risk among school-aged children in Côte d′Ivoire and a strong empirical basis for a rational targeting of control interventions.
Author Summary
Two types of blood-dwelling parasitic worms that cause schistosomiasis (i.e., Schistosoma haematobium and Schistosoma mansoni) are endemic in Côte d′Ivoire, West Africa. Reliable information on their geographical distribution is needed to plan and guide the national control program. Recently, control efforts have been intensified. There is a need to update risk maps that, historically, have been based on data specific to each type of parasite. In late 2011 and early 2012, we conducted a cross-sectional survey in 92 schools all over Côte d′Ivoire. We used Bayesian geostatistical multinomial models to estimate the risk for each infection, as well as co-infection. We estimated that slightly less than 10% of school-aged children are affected by schistosomiasis (5.3% with S. haematobium and 3.8% with S. mansoni). To control schistosomiasis with the deworming drug praziquantel, approximately 2 million treatments would be necessary each year. The distinct spatial patterns of S. haematobium and S. mansoni imply that co-infection with these two types of parasitic worms is rare across the country. Our results provide a detailed analysis of the spatial distribution of schistosomiasis risk among school-aged children in Côte d′Ivoire, which will inform the national control program for targeted interventions.
doi:10.1371/journal.pntd.0003407
PMCID: PMC4270510  PMID: 25522007
12.  Fecal Occult Blood and Fecal Calprotectin as Point-of-Care Markers of Intestinal Morbidity in Ugandan Children with Schistosoma mansoni Infection 
Background
Calprotectin is a calcium-binding cytoplasmic protein found in neutrophils and increasingly used as a marker of bowel inflammation. Fecal occult blood (FOB) is also a dependable indicator of bowel morbidity. The objective of our study was to determine the applicability of these tests as surrogate markers of Schistosoma mansoni intestinal morbidity before and after treatment with praziquantel (PZQ).
Methods
216 children (ages 3–9 years old) from Buliisa District in Lake Albert, Uganda were examined and treated with PZQ at baseline in October 2012 with 211 of them re-examined 24 days later for S. mansoni and other soil transmitted helminths (STH). POC calprotectin and FOB assays were performed at both time points on a subset of children. Associations between the test results and infection were analysed by logistic regression.
Results
Fecal calprotectin concentrations of 150–300 µg/g were associated with S. mansoni egg patent infection both at baseline and follow up (OR: 12.5 P = 0.05; OR: 6.8 P = 0.02). FOB had a very strong association with baseline anemia (OR: 9.2 P = 0.03) and medium and high egg intensity schistosomiasis at follow up (OR: 6.6 P = 0.03; OR: 51.3 P = 0.003). Both tests were strongly associated with heavy intensity S. mansoni infections. There was a significant decrease in FOB and calprotectin test positivity after PZQ treatment in those children who had egg patent schistosomiasis at baseline.
Conclusions
Both FOB and calprotectin rapid assays were found to correlate positively and strongly with egg patent S. mansoni infection with a positive ameloriation response after PZQ treatment indicative of short term reversion of morbidity. Both tests were appropriate for use in the field with excellent operational performance and reliability. Due to its lower-cost which makes its scale-up of use affordable, FOB could be immediately adopted as a monitoring tool for PC campaigns for efficacy evaluation before and after treatment.
Author Summary
The severity of intestinal schistosomiasis, a disease caused by Schistosoma mansoni infection, is likely under-reported in part due to the scarcity of field-appropriate morbidity markers. Downstream potential complications of this disease include anemia, failure to thrive, and chronic multi-organ damage. Point-of-care (POC) tools to monitor intestinal schistosomiasis in low resource settings are urgently needed to better quantify the burden of disease in endemic countries and to gauge the clinical impact of scale-up of preventive PC. For the present study in rural Uganda, fecal occult blood and fecal calprotectin were identified as potential surrogate markers of intestinal morbidity. We tested both POC tests and found that they were both associated with active schistosomiasis as detected by eggs in stool with significant decrease in test positivity after PZQ treatment demonstrating short term morbidity reversion. Calprotectin was a strong indicator of intestinal inflammation, however, owing to its high per-test price makes it difficult to scale-up accordingly. Conversely, fecal occult blood was technically feasible, low-cost and had optimal performance as a morbidity marker, hence we strongly advocate for its immediate inclusion as a monitoring tool for PC programs.
doi:10.1371/journal.pntd.0002542
PMCID: PMC3828154  PMID: 24244777
13.  A Very High Infection Intensity of Schistosoma mansoni in a Ugandan Lake Victoria Fishing Community Is Required for Association with Highly Prevalent Organ Related Morbidity 
Background
In schistosomiasis control programmes using mass chemotherapy, epidemiological and morbidity aspects of the disease need to be studied so as to monitor the impact of treatment, and make recommendations accordingly. These aspects were examined in the community of Musoli village along Lake Victoria in Mayuge district, highly endemic for Schistosoma mansoni infection.
Methodology and Principal Findings
A cross sectional descriptive study was undertaken in a randomly selected sample of 217 females and 229 males, with a mean age of 26 years (SD ±16, range 7–76 years). The prevalence of S. mansoni was 88.6% (95% CI: 85.6–91.5). The geometric mean intensity (GMI) of S. mansoni was 236.2 (95% CI: 198.5–460.9) eggs per gram (epg) faeces. Males had significantly higher GMI (370.2 epg) than females (132.6 epg) and age was also significantly associated with intensity of infection. Levels of water contact activities significantly influenced intensity of infection and the highest intensity of infection was found among people involved in fishing. However, organomegaly was not significantly associated with S. mansoni except for very heavy infection (>2000 epg). Liver image patterns C and D indicative of fibrosis were found in only 2.2% and 0.2%, respectively. S. mansoni intensity of infection was associated with portal vein dilation and abnormal spleen length. Anaemia was observed in 36.4% of the participants but it was not associated with S. mansoni infection intensity. Considering growth in children as one of the morbidity indicators of schistosomiasis, intensity of S. mansoni was significantly associated with stunting.
Conclusion
Although organ-related morbidity, with the exception of periportal fibrosis, and S. mansoni infections were highly prevalent, the two were only associated for individuals with very high infection intensities. These results contrast starkly with reports from Ugandan Lake Albert fishing communities in which periportal fibrosis is more prevalent.
Author Summary
Schistosoma mansoni infection is one of the Neglected Tropical Diseases (NTDs) that perpetuate poverty, especially in Sub Saharan Africa. It is associated with hepatomegaly, splenomegaly or hepatosplenomegaly, liver fibrosis and anaemia. Control of schistosomiasis is now a priority in most endemic countries in Africa as a component of integrated control of NTDs using mass drug administration (MDA). Other than the new WHO strategic plan to eliminate schistosomiasis as a public health problem in WHO Africa region by 2020, the major target in the control of schistosomiasis has for a long time been reduction of its related morbidity. Epidemiological and morbidity studies are key in monitoring the impact of an intervention. However, epidemiology of schistosomiasis and its related morbidity have been shown to vary in different endemic areas and communities. We report on the epidemiology of S. mansoni infection and related morbidity in a community in Mayuge District along Lake Victoria in Uganda.
doi:10.1371/journal.pntd.0002268
PMCID: PMC3723538  PMID: 23936559
14.  Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement 
PLoS Pathogens  2014;10(1):e1003878.
Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni.
Author Summary
The bloodfluke Schistosoma mansoni causes human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. There is no vaccine for schistosomiasis, and chemotherapy relies heavily on a single drug, praziquantel. With only one drug available, the prospect of drug resistance is a serious concern, particularly when praziquantel usage is on the rise due to mass treatment programs in many parts of the world. There is a pressing need to identify new drug targets and to develop new chemotherapeutics for schistosomiasis. The focus of this research is on the nervous system of S. mansoni. Many pesticides and antiparasitic drugs act by interacting with neuronal proteins and therefore the nervous system holds great promise for drug discovery. Here we describe a new protein that is present in the nervous system of S. mansoni and regulates movement of the worm. The protein was further identified as a specific receptor for serotonin, an important neurotransmitter and a known modulator of motility in schistosomes. This work shows that the serotonin receptor of S. mansoni is required for proper motor control and therefore is a potential target for chemotherapeutic intervention.
doi:10.1371/journal.ppat.1003878
PMCID: PMC3894222  PMID: 24453972
15.  A Latent Markov Modelling Approach to the Evaluation of Circulating Cathodic Antigen Strips for Schistosomiasis Diagnosis Pre- and Post-Praziquantel Treatment in Uganda 
PLoS Computational Biology  2013;9(12):e1003402.
Regular treatment with praziquantel (PZQ) is the strategy for human schistosomiasis control aiming to prevent morbidity in later life. With the recent resolution on schistosomiasis elimination by the 65th World Health Assembly, appropriate diagnostic tools to inform interventions are keys to their success. We present a discrete Markov chains modelling framework that deals with the longitudinal study design and the measurement error in the diagnostic methods under study. A longitudinal detailed dataset from Uganda, in which one or two doses of PZQ treatment were provided, was analyzed through Latent Markov Models (LMMs). The aim was to evaluate the diagnostic accuracy of Circulating Cathodic Antigen (CCA) and of double Kato-Katz (KK) faecal slides over three consecutive days for Schistosoma mansoni infection simultaneously by age group at baseline and at two follow-up times post treatment. Diagnostic test sensitivities and specificities and the true underlying infection prevalence over time as well as the probabilities of transitions between infected and uninfected states are provided. The estimated transition probability matrices provide parsimonious yet important insights into the re-infection and cure rates in the two age groups. We show that the CCA diagnostic performance remained constant after PZQ treatment and that this test was overall more sensitive but less specific than single-day double KK for the diagnosis of S. mansoni infection. The probability of clearing infection from baseline to 9 weeks was higher among those who received two PZQ doses compared to one PZQ dose for both age groups, with much higher re-infection rates among children compared to adolescents and adults. We recommend LMMs as a useful methodology for monitoring and evaluation and treatment decision research as well as CCA for mapping surveys of S. mansoni infection, although additional diagnostic tools should be incorporated in schistosomiasis elimination programs.
Author Summary
Schistosomiasis remains one of the most prevalent parasitic diseases in developing countries, with Schistosoma mansoni being the most widespread of the human-infecting schistosomes. For the routine surveillance of human S. mansoni infection more “field-applicable,” sensitive, and cost-effective diagnostics that replicate faecal samples over several consecutive days [the Kato-Katz (KK) method], are needed. We propose a statistical modelling framework in order to evaluate the diagnostic performance of the urine strip test for Circulating Cathodic Antigen (CCA) and single-day double KK measurements over three consecutive days for the diagnosis of S. mansoni infection in two different age groups from Uganda pre- and post- praziquantel (PZQ) treatment. We demonstrate that CCA is an appropriate tool for mapping surveys of S. mansoni infection. Our findings should allow for evaluation of the risk of potential misinterpretation with regards to diagnosis of S. mansoni infection through CCA or KK in this endemic setting pre- and post- PZQ treatment as the numbers and infection intensities are brought down, bridging existing important gaps in schistosomiasis diagnostics research. More generally, the proposed statistical analysis can reveal important biological insights from other diseases without gold standard diagnostic tools whenever longitudinal data are available.
doi:10.1371/journal.pcbi.1003402
PMCID: PMC3868541  PMID: 24367250
16.  Atypical presentation of cerebral schistosomiasis four years after exposure to Schistosoma mansoni☆ 
Schistosomiasis is the second most socioeconomically devastating parasitic disease worldwide, affecting over 240 million people in 77 countries on 5 continents and killing 300,000 people annually in sub-Saharan Africa alone. Neuroschistosomiasis is caused by granuloma formation around eggs that lodge in the CNS, with Schistosoma mansoni and Schistosoma haematobium usually affecting the spinal cord and Schistosoma japonicum causing most reported cerebral disease. We report a case of a previously healthy 25-year-old woman native to the United States who presented with a single generalized tonic–clonic seizure without other neurologic symptoms four years after spending a semester in Ghana where she went swimming once in a river. Brain MRI showed areas of signal abnormality and mottled nodular linear enhancement in the left temporal and right posterior temporal/parietal lobes and right cerebellum without mass effect. A biopsy of the left temporal lesion showed prominent granulomas with dense mixed inflammatory infiltrates composed of eosinophils, plasma cells, and lymphocytes surrounding refractile egg shells containing characteristic embryonal cells and von Lichtenberg's envelope and displaying the pathognomonic spine shape of S. mansoni. Serum ELISA and antibody immunoblots confirmed exposure to S. mansoni. In summary, we describe the atypical combination of cerebral schistosomiasis due to S. mansoni, after a prolonged interval of four years, from a single known exposure.
doi:10.1016/j.ebcr.2014.01.006
PMCID: PMC4308089  PMID: 25667876
Cerebral schistosomiasis; Neuroschistosomiasis; Schistosoma mansoni; Generalized tonic–clonic seizure; Granuloma
17.  Schistosoma mansoni Tegument Protein Sm29 Is Able to Induce a Th1-Type of Immune Response and Protection against Parasite Infection 
Background
Schistosomiasis continues to be a significant public health problem. This disease affects 200 million people worldwide and almost 800 million people are at risk of acquiring the infection. Although vaccine development against this disease has experienced more failures than successes, encouraging results have recently been obtained using membrane-spanning protein antigens from the tegument of Schistosoma mansoni. Our group recently identified Sm29, another antigen that is present at the adult worm tegument surface. In this study, we investigated murine cellular immune responses to recombinant (r) Sm29 and tested this protein as a vaccine candidate.
Methods and Findings
We first show that Sm29 is located on the surface of adult worms and lung-stage schistosomula through confocal microscopy. Next, immunization of mice with rSm29 engendered 51%, 60% and 50% reduction in adult worm burdens, in intestinal eggs and in liver granuloma counts, respectively (p<0.05). Protective immunity in mice was associated with high titers of specific anti-Sm29 IgG1 and IgG2a and elevated production of IFN-γ, TNF-α and IL-12, a typical Th1 response. Gene expression analysis of worms recovered from rSm29 vaccinated mice relative to worms from control mice revealed a significant (q<0.01) down-regulation of 495 genes and up-regulation of only 22 genes. Among down-regulated genes, many of them encode surface antigens and proteins associated with immune signals, suggesting that under immune attack schistosomes reduce the expression of critical surface proteins.
Conclusion
This study demonstrates that Sm29 surface protein is a new vaccine candidate against schistosomiasis and suggests that Sm29 vaccination associated with other protective critical surface antigens is the next logical strategy for improving protection.
Author Summary
Schistosomiasis is the most important human helminth infection in terms of morbidity and mortality. Although the efforts to develop a vaccine against this disease have experienced failures, a new generation of surface antigens revealed by proteomic studies changed this scenario. Our group has characterized the protein Sm29 described previously as one of the most exposed and expressed antigens in the outer tegument of Schistosoma mansoni. Studies in patients living in endemic areas for schistosomiasis revealed high levels of IgG1 and IgG3 anti-Sm29 in resistant individuals. In this study, confocal microscope analysis showed Sm29 present in the surface of lung-stage schistosoluma and adult worms. Recombinant Sm29, when used as vaccine candidate, induced high levels of protection in mice. This protection was associated with a typical Th1 immune response and reduction of worm burden, liver granulomas and in intestinal eggs. Further, microarray analysis of worms recovered from vaccinated mice showed significant down-regulation of several genes encoding previously characterized vaccine candidates and/or molecules exposed on the surface, suggesting an immune evasion strategy of schistosomes under immune attack. These results demonstrated that Sm29 as one of the important antigens with potential to compose a vaccine against schistosomiasis.
doi:10.1371/journal.pntd.0000308
PMCID: PMC2553283  PMID: 18827884
18.  New Insights into the Molecular Epidemiology and Population Genetics of Schistosoma mansoni in Ugandan Pre-school Children and Mothers 
Significant numbers of pre-school children are infected with Schistosoma mansoni in sub-Saharan Africa and are likely to play a role in parasite transmission. However, they are currently excluded from control programmes. Molecular phylogenetic studies have provided insights into the evolutionary origins and transmission dynamics of S. mansoni, but there has been no research into schistosome molecular epidemiology in pre-school children. Here, we investigated the genetic diversity and population structure of S. mansoni in pre-school children and mothers living in lakeshore communities in Uganda and monitored for changes over time after praziquantel treatment. Parasites were sampled from children (<6 years) and mothers enrolled in the longitudinal Schistosomiasis Mothers and Infants Study at baseline and at 6-, 12- and 18-month follow-up surveys. 1347 parasites from 35 mothers and 45 children were genotyped by direct sequencing of the cytochrome c oxidase (cox1) gene. The cox1 region was highly diverse with over 230 unique sequences identified. Parasite populations were genetically differentiated between lakes and non-synonymous mutations were more diverse at Lake Victoria than Lake Albert. Surprisingly, parasite populations sampled from children showed a similar genetic diversity to those sampled from mothers, pointing towards a non-linear relationship between duration of exposure and accumulation of parasite diversity. The genetic diversity six months after praziquantel treatment was similar to pre-treatment diversity. Our results confirm the substantial genetic diversity of S. mansoni in East Africa and provide significant insights into transmission dynamics within young children and mothers, important information for schistosomiasis control programmes.
Author Summary
Many pre-school children in sub-Saharan Africa are infected with the parasite Schistosoma mansoni, which causes intestinal schistosomiasis. However, there has been no work published on the molecular epidemiology of Schistosoma in children under six or the role that these children play in parasite transmission. We analysed the genetic structure of parasite populations collected from mothers and young children living on the shores of Lakes Albert and Victoria in Uganda. Parasite populations were different at the two lakes indicating that there is little flow of parasite genes between the lakes. We were surprised to discover a large amount of genetic variation in parasites sampled from both children and mothers, suggesting that genetic variation is not directly related to duration of exposure to infested water. In addition, we found some evidence that young children are involved in S. mansoni transmission. The substantial genetic variation of S. mansoni in young children suggests that these parasites could be operating as a source of a variety of genetic traits, including drug susceptibility. Overall our findings offer significant insights into population genetics of S. mansoni in pre-school children and their mothers and provide important information for effective control of intestinal schistosomiasis.
doi:10.1371/journal.pntd.0002561
PMCID: PMC3861247  PMID: 24349589
19.  Evidence of Long Term Benefit of Morbidity Reduction Due to Praziquantel Treatment Against Schistosoma Mansoni in Kigungu Fishing Village in Entebbe, Uganda 
Praziquantel (PZQ) is efficacious against Schistosoma mansoni. This was prospective cohort study. This study was carried out at Kigungu fishing village, Entebbe, Uganda. The goal of the study was to establish cost effective regiment for mass drug administration (MDA) of Praziquentel in the morbidity reduction of S.mansoni infection. In January 2004, nine hundred and forty five (945) participants were registered in this study. Our analysis was based on examining microscopically three slides prepared from each of 945 stool specimens delivered by each of the participant using modified Kato/Katz method. These included male and female, children and adults living in Kigungu fishing village in Entebbe Uganda. In total 901, cohorts were re-examined for infections clearance six months later in July 2004 and 18 months later in June 2005, 625 cohorts were again re-evaluated for S.mansoni infections after the baseline study. At baseline, (448) of 945 (47.5%) cohorts were S. mansoni positive. All these participants were treatment with a single oral dose of praziquantel at 40mg/kg. At the same time, 495 (52.5%) were S. mansoni negative. Of the 625 (66.3%) cohorts who came back for final review, 80 (12.8%) were still positive for S. mansoni while 210 (33.6%) remained negative after the base line treatment with praziquantel. On the other hand 103 (16.3%) of cohorts who were initially negative at the base line became S.mansoni positive after 18 months and 213(34.1%) remained negative for S.mansoni. The force of re-infection after six months was significant {(P=0.0001), (OR 0.47) CI at 95% (0.31–0.71)}. Nevertheless the force of reinfection was not significant after 18 months {(P=0.766), (OR 0.95) CI at 95% (0.68–1.34)}.The geometric mean eggs excretion of the 80 cohorts who were S.mansoni positive at 18 months was 151.967.This did not reach the geometric mean egg excreted by the same cohorts at baseline which was 285.05. The egg excretion was reduced by 46.8%. Similarly there was marked decrease in clinical symptoms amongst the cohorts. Our study suggests evidence of long-term benefit of praziquantel in Kigungu and that a yearly administration of praziquantel to the community could be a regiment for mass drug administration (MAD) for this community to control schistosomiasis morbidity.
PMCID: PMC3497845  PMID: 23878705
20.  Sm10.3, a Member of the Micro-Exon Gene 4 (MEG-4) Family, Induces Erythrocyte Agglutination In Vitro and Partially Protects Vaccinated Mice against Schistosoma mansoni Infection 
Background
The parasitic flatworm Schistosoma mansoni is a blood fluke that causes schistosomiasis. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control disease is a combination of drug treatment and immunization with an anti-schistosome vaccine. Numerous antigens that are expressed at the interface between the parasite and the mammalian host have been assessed. Among the most promising molecules are the proteins present in the tegument and digestive tract of the parasite.
Methodology/Principal Findings
In this study, we evaluated the potential of Sm10.3, a member of the micro-exon gene 4 (MEG-4) family, for use as part of a recombinant vaccine. We confirmed by real-time PCR that Sm10.3 was expressed at all stages of the parasite life cycle. The localization of Sm10.3 on the surface and lumen of the esophageal and intestinal tract in adult worms and lung-stage schistosomula was confirmed by confocal microscopy. We also show preliminary evidence that rSm10.3 induces erythrocyte agglutination in vitro. Immunization of mice with rSm10.3 induced a mixed Th1/Th2-type response, as IFN-γ, TNF-α, and low levels of IL-5 were detected in the supernatant of cultured splenocytes. The protective effect conferred by vaccination with rSm10.3 was demonstrated by 25.5–32% reduction in the worm burden, 32.9–43.6% reduction in the number of eggs per gram of hepatic tissue, a 23.8% reduction in the number of granulomas, an 11.8% reduction in the area of the granulomas and a 39.8% reduction in granuloma fibrosis.
Conclusions/Significance
Our data suggest that Sm10.3 is a potential candidate for use in developing a multi-antigen vaccine to control schistosomiasis and provide the first evidence for a possible role for Sm10.3 in the blood feeding process.
Author Summary
Schistosomiasis mainly occurs in developing countries and is the most important human helminth infection in terms of global mortality. This parasitic disease affects more than 200 million people worldwide and causes more than 250,000 deaths per year. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy for controlling schistosomiasis is a combination of drug treatment and immunization with an anti-schistosome vaccine. Consequently, significant effort has been dedicated to developing and characterizing an anti-schistosome vaccine. Over the last five years, considerable data have been generated regarding the genomics, transcriptomics and proteomics of Schistosoma mansoni. In the present study, we characterize the Sm10.3 protein and evaluate its potential to protect against S. mansoni infection in a murine model. We demonstrate that Sm10.3 is primarily expressed during the stages of the parasite life cycle that involve infection and disease development in the human host. Sm10.3 is located on the surface of the digestive epithelia of adult female worms, an important host/parasite interface. Moreover, the vaccination of mice with rSm10.3 confers partial protection against S. mansoni. Taken together, our data suggest that Sm10.3 may be a useful component of a multi-antigen vaccine against schistosomiasis.
doi:10.1371/journal.pntd.0002750
PMCID: PMC3961193  PMID: 24651069
21.  Use of Genomic DNA as an Indirect Reference for Identifying Gender-Associated Transcripts in Morphologically Identical, but Chromosomally Distinct, Schistosoma mansoni Cercariae 
Background
The use of DNA microarray technology to study global Schistosoma gene expression has led to the rapid identification of novel biological processes, pathways or associations. Implementation of standardized DNA microarray protocols across laboratories would assist maximal interpretation of generated datasets and extend productive application of this technology.
Methodology/Principal Findings
Utilizing a new Schistosoma mansoni oligonucleotide DNA microarray composed of 37,632 elements, we show that schistosome genomic DNA (gDNA) hybridizes with less variation compared to complex mixed pools of S. mansoni cDNA material (R = 0.993 for gDNA compared to R = 0.956 for cDNA during ‘self versus self’ hybridizations). Furthermore, these effects are species-specific, with S. japonicum or Mus musculus gDNA failing to bind significantly to S. mansoni oligonucleotide DNA microarrays (e.g R = 0.350 when S. mansoni gDNA is co-hybridized with S. japonicum gDNA). Increased median fluorescent intensities (209.9) were also observed for DNA microarray elements hybridized with S. mansoni gDNA compared to complex mixed pools of S. mansoni cDNA (112.2). Exploiting these valuable characteristics, S. mansoni gDNA was used in two-channel DNA microarray hybridization experiments as a common reference for indirect identification of gender-associated transcripts in cercariae, a schistosome life-stage in which there is no overt sexual dimorphism. This led to the identification of 2,648 gender-associated transcripts. When compared to the 780 gender-associated transcripts identified by hybridization experiments utilizing a two-channel direct method (co-hybridization of male and female cercariae cDNA), indirect methods using gDNA were far superior in identifying greater quantities of differentially expressed transcripts. Interestingly, both methods identified a concordant subset of 188 male-associated and 156 female-associated cercarial transcripts, respectively. Gene ontology classification of these differentially expressed transcripts revealed a greater diversity of categories in male cercariae. Quantitative real-time PCR analysis confirmed the DNA microarray results and supported the reliability of this platform for identifying gender-associated transcripts.
Conclusions/Significance
Schistosome gDNA displays characteristics highly suitable for the comparison of two-channel DNA microarray results obtained from experiments conducted independently across laboratories. The schistosome transcripts identified here demonstrate, for the first time, that gender-associated patterns of expression are already well established in the morphologically identical, but chromosomally distinct, cercariae stage.
Author Summary
Infection with parasitic schistosome worms causes schistosomiasis, a major neglected tropical disease currently affecting millions of individuals living in the developing world. A virtually unique characteristic of the schistosome life style in comparison to other members of the Phylum Platyhelminthes is that schistosomes are dioecious, having both male and female individuals. While much is known about the adult dioecious state, virtually nothing has been established with regard to the dioecious larval stages such as the snail-infective miracidium and the human-infective cercaria. To shed some light on this under-studied area of schistosome biology, we first developed a new long-oligonucleotide DNA microarray and used this tool to perfect an indirect hybridization strategy utilizing schistosome genomic DNA for large-scale transcription investigations. Second, we used this tool and strategy to characterize the gene expression profiles of infective male and female cercarial life-stages. This led to the identification of several thousand differentially expressed transcripts and demonstrated that gender-associated patterns of transcription (some associated with adult-specific activities) are surprisingly already established in this short-lived larval life-stage. Further functional interrogation of these transcripts will generate a more complete picture of factors and processes underlying the schistosome's dioecious state, which may help in control strategies attempting to prevent sexual maturation, inhibit male–female interactions and limit the production of tissue-damaging eggs.
doi:10.1371/journal.pntd.0000323
PMCID: PMC2565838  PMID: 18941520
22.  Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection 
Parasites & Vectors  2013;6:199.
Background
Hepatic schistosomiasis is considered to be one of the most prevalent forms of chronic liver disease in the world due to its complication of liver fibrosis. The demonstration of the pro-fibrogenic role of angiotensin (Ang) II in chronic liver disease brought up the idea that anti-Ang II agents may be effective in improving hepatic fibrosis by either blocking Ang II type 1 (AT1) receptors or inhibiting the angiotensin converting enzyme. Peroxisome proliferator-activated receptors gamma (PPARγ) activation has been also shown to inhibit hepatic stellate cell activation and progression of fibrosis. The present study has aimed at testing the anti-fibrogenic effects of telmisartan; an AT1 receptor blocker and a PPARγ partial agonist, alone or combined with praziquantel (PZQ) on Schistosoma mansoni-induced liver fibrosis in mice.
Methods
To achieve the aim of the study, two sets of experiments were performed in which telmisartan was initiated at the 5th (set 1) and the 10th (set 2) weeks post infection to assess drug efficacy in both acute and chronic stages of liver fibrosis, respectively. Schistosoma mansoni-infected mice were randomly divided into the following four groups: infected-control (I), telmisartan-treated (II), PZQ-treated (III), and telmisartan+PZQ-treated (IV). In addition, a normal non-infected group was used for comparison. Parasitological (hepatomesenteric worm load and oogram pattern), histopathological, morphometric, immunohistochemical (hepatic expressions of matrix metalloproteinase-2; MMP-2 and tissue inhibitor of metalloproteinase-2; TIMP-2), and biochemical (serum transforming growth factor beta 1; TGF-β1 and liver function tests) studies were performed.
Results
Telmisartan failed to improve the parasitological parameters, while it significantly (P<0.05) decreased the mean granuloma diameter, area of fibrosis, and serum TGF-β1. Additionally, telmisartan increased MMP-2 and decreased TIMP-2 hepatic expression. Combined treatment failed to show any additive properties, yet it did not affect the anti-schistosomal activity of PZQ.
Conclusions
These results suggest potential anti-fibrotic effects of telmisartan, an AT1 receptor blocker and a PPARγ partial agonist, in acute and chronic stages of Schistosoma mansoni–induced liver fibrosis in mice.
doi:10.1186/1756-3305-6-199
PMCID: PMC3733928  PMID: 23829789
Hepatic fibrosis; Schistosoma mansoni; Telmisartan; MMP-2; TIMP-2; TGF-β1
23.  Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols 
Background
The parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches.
Methodology/Principal Findings
Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11th to 17th day after infection caused significant decreases in worm burden (39%–61%) and egg production (42%–98%). Hz formation was significantly inhibited (40%–65%) in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms.
Conclusions
The overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.
Author Summary
Heme is an essential molecule to most living organisms, but once in a free state it exerts toxic effects. Blood-feeding organisms evolved efficient ways to detoxify free heme derived from hemoglobin digestion. A key mechanism present in some hematophagous organisms consists of the crystallization of heme into a pigment named hemozoin. Schistosoma mansoni is one of the etiologic agents of human schistosomiasis, a parasitic disease that affects over 200 million people in tropical and subtropical areas. Hemozoin formation represents the main heme detoxification pathway in S. mansoni. Here, we report that the antimalarial quinoline methanols quinine and quinidine exert schistosomicidal effects notably due to their capacity to interfere with hemozoin formation. When quinine or quinidine were administered intraperitoneally during seven days to S. mansoni-infected mice (75 mg/kg/day), both worm and eggs burden were significantly reduced. Interestingly, hemozoin content in female worms was drastically affected after treatment with either compound. We also found that quinine caused important changes in the cellular organization of worm gastrodermis and increased expression of genes related to musculature, protein synthesis and repair mechanisms. Together, our results indicate that interference with hemozoin formation is a valid chemotherapeutic target for development of new schistosomicidal agents.
doi:10.1371/journal.pntd.0000477
PMCID: PMC2703804  PMID: 19597543
24.  Omega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo 
Nature Communications  2014;5:5375.
Schistosomiasis, one of the most important neglected tropical diseases worldwide, is caused by flatworms (blood flukes or schistosomes) that live in the bloodstream of humans. The hepatointestinal form of this debilitating disease results from a chronic infection with Schistosoma mansoni or Schistosoma japonicum. No vaccine is available to prevent schistosomiasis, and treatment relies predominantly on the use of a single drug, praziquantel. In spite of considerable research effort over the years, very little is known about the complex in vivo events that lead to granuloma formation and other pathological changes during infection. Here we use, for the first time, a lentivirus-based transduction system to deliver microRNA-adapted short hairpin RNAs (shRNAmirs) into the parasite to silence and explore selected protein-encoding genes of S. mansoni implicated in the disease process. This gene-silencing system has potential to be used for functional genomic–phenomic studies of a range of socioeconomically important pathogens.
Schistosomiasis, a neglected tropical disease, is caused by flatworms such as Schistosoma mansoni. Here, Hagen et al. describe a lentivirus-based transduction system to deliver microRNA-adapted small hairpin RNAs into S. mansoni to inhibit transcription of selected genes implicated in the disease process.
doi:10.1038/ncomms6375
PMCID: PMC4243216  PMID: 25400038
25.  Development and Validation of a Luminescence-based, Medium-Throughput Assay for Drug Screening in Schistosoma mansoni 
PLoS Neglected Tropical Diseases  2015;9(1):e0003484.
Background
Schistosomiasis, one of the world’s greatest neglected tropical diseases, is responsible for over 280,000 human deaths per annum. Praziquantel, developed in the 1970s, has high efficacy, excellent tolerability, few and transient side effects, simple administration procedures and competitive cost and it is currently the only recommended drug for treatment of human schistosomiasis. The use of a single drug to treat a population of over 200 million infected people appears particularly alarming when considering the threat of drug resistance. Quantitative, objective and validated methods for the screening of compound collections are needed for the discovery of novel anti-schistosomal drugs.
Methodology/Principal Findings
The present work describes the development and validation of a luminescence-based, medium-throughput assay for the detection of schistosomula viability through quantitation of ATP, a good indicator of metabolically active cells in culture. This validated method is demonstrated to be fast, highly reliable, sensitive and automation-friendly. The optimized assay was used for the screening of a small compound library on S. mansoni schistosomula, showing that the proposed method is suitable for a medium-throughput semi-automated screening. Interestingly, the pilot screening identified hits previously reported to have some anti-parasitic activity, further supporting the validity of this assay for anthelminthic drug discovery.
Conclusions
The developed and validated schistosomula viability luminescence-based assay was shown to be successful and suitable for the identification of novel compounds potentially exploitable in future schistosomiasis therapies.
Author Summary
Schistosomiasis, one of the world’s greatest human neglected tropical diseases, is caused by a parasitic flatworm trematode of the genus Schistosoma. Among human parasitic diseases, schistosomiasis ranks second behind malaria in terms of socio-economic and public health importance in tropical and subtropical areas. More than 200 million people are currently infected in 77 countries, 85% of whom live in sub-Saharian Africa. To date no vaccine is available against schistosomiasis. As chemotherapy relies on a single drug, praziquantel, many initiatives have been promoted aiming to search for novel anti-schistosomal drugs that can represent a valid alternative to the current treatment or could be used in case of emerging resistance. Quantitative, objective and validated methods for compound collections screening are needed for the discovery of novel anti-schistosomal drugs. Here, we report the development and validation of a medium-throughput, luminescence-based assay for assessing viability at the schistosomulum stage of the human parasite S. mansoni. Our methodology enables a simple, reproducible, highly sensitive and objective quantitation of parasite viability. It is also automation compatible and enables the screening of compound collections thus hopefully contributing to the discovery of novel therapeutic strategies against schistosomiasis.
doi:10.1371/journal.pntd.0003484
PMCID: PMC4312041  PMID: 25635836

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