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1.  Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on intensity of infection and antibody responses to schistosome antigens: results of a randomised, placebo-controlled trial 
Background
Praziquantel treatment of schistosomiasis during pregnancy was only recommended in 2002; hence the effects of treatment during pregnancy are not fully known. We have therefore evaluated the effects on infection intensity and the immunological effects of praziquantel treatment against Schistosoma mansoni during pregnancy, compared with treatment after delivery.
Methods
A nested cohort of 387 Schistosoma mansoni infected women was recruited within a larger trial of de-worming during pregnancy. Women were randomised to receive praziquantel or placebo during pregnancy. All women were treated after delivery. Infection intensity after treatment was assessed by a single Kato-Katz examination of stool samples with duplicate slides and categorised as undetected, light (1–99 eggs per gram (epg)), moderate (100–399 epg) or heavy (≥400 epg). Antibodies against S. mansoni worm and egg antigens were measured by ELISA. Results were compared between women first treated during pregnancy and women first treated after delivery.
Results
At enrolment, 252 (65.1%) of the women had light infection (median (IQR) epg: 35 (11, 59)), 75 (19.3%) moderate (median (IQR) epg: 179(131, 227)) and 60 (15.5%) had heavy infection (median (IQR) epg: 749 (521, 1169)) with S. mansoni. At six weeks after praziquantel treatment during pregnancy S. mansoni infection was not detectable in 81.9% of the women and prevalence and intensity had decreased to 11.8% light, 4.7% moderate and 1.6% heavy a similar reduction when compared with those first treated after delivery (undetected (88.5%), light (10.6%), moderate (0.9%) and heavy (0%), p = 0.16). Parasite specific antibody levels were lower during pregnancy than after delivery. Praziquantel treatment during pregnancy boosted anti-worm IgG isotypes and to a lesser extent IgE, but these boosts were less pronounced than in women whose treatment was delayed until after delivery. Praziquantel had limited effects on antibodies against egg antigens.
Conclusion
S mansoni antigen-specific antibody levels and praziquantel-induced boosts in antibody levels were broadly suppressed during pregnancy, but this was not associated with major reduction in the efficacy of praziquantel. Long-term implications of these findings in relation to resistance to re-infection remain to be explored.
Trial registration
International Standard Randomised Controlled Trial Number for the current study: ISRCTN32849447 http://www.controlled-trials.com/ISRCTN32849447/elliott
doi:10.1186/1471-2334-9-32
PMCID: PMC2666740  PMID: 19296834
2.  Cytokine Pattern of T Lymphocytes in Acute Schistosomiasis mansoni Patients following Treated Praziquantel Therapy 
Acute schistosomiasis is associated with a primary exposure and is more commonly seen in nonimmune individuals traveling through endemic regions. In this study, we have focused on the cytokine profile of T lymphocytes evaluated in circulating leukocytes of acute Schistosomiasis mansoni-infected patients (ACT group) before and after praziquantel treatment (ACT-TR group). Our data demonstrated increased values of total leukocytes, eosinophils, and monocytes in both groups. Interestingly, we have observed that patients treated with praziquantel showed increased values of lymphocytes as compared with noninfected group (NI) or ACT groups. Furthermore, a decrease of neutrophils in ACT-TR was observed when compared to ACT group. Analyses of short-term in vitro whole blood stimulation demonstrated that, regardless of the presence of soluble Schistosoma mansoni eggs antigen (SEA), increased synthesis of IFN-γ and IL-4 by T-cells was observed in the ACT group. Analyses of cytokine profile in CD8 T cells demonstrated higher percentage of IFN-γ and IL-4 cells in both ACT and ACT-TR groups apart from increased percentage of IL-10 cells only in the ACT group. This study is the first one to point out the relevance of CD8 T lymphocytes in the immune response induced during the acute phase of schistosomiasis.
doi:10.1155/2013/909134
PMCID: PMC3563181  PMID: 23401741
3.  Imported CNS schistosomiasis--a case report. 
Central nervous system (CNS) involvement may occur in chronic schistosomiasis. It can be produced by any Schistosome species but happens most frequently in chronic Schistosoma japonicum infection. CNS involvement by S. mansoni is relatively rare but it may occur by embolization of eggs or ectopic migration of adult worms. A case of cerebral schistosomiasis caused by S. mansoni in a 40-year-old man, who had worked in Yemen, is reported. Biopsies taken from the cerebellar vermis and the roof of the fourth ventricle, showed granulomatous inflammation due to eggs. S. mansoni was identified by stool examination and ELISA using serum and CSF. This is the first imported case of cerebral schistosomiasis in Korea.
PMCID: PMC3054130  PMID: 7598827
4.  T Regulatory Cell Levels Decrease in People Infected With Schistosoma mansoni on Effective Treatment 
Schistosomiasis mansoni is usually a chronic infection that leads to long-term, systemic exposure to schistosome antigens. Experimental Schistosoma mansoni infection is associated with immunoregulatory mechanisms, including T regulatory cells (Treg) that may help control morbidity and dampen resistance to re-infection. We now show that some schistosomiasis mansoni patients have high proportions of CD3+/CD4+/CD25high Treg. On effective treatment with praziquantel, these high Treg percentages decrease, and fewer of the remaining Treg express CD45RO. The proportion of Treg in S. mansoni–infected patients is inversely related to their percentage of activated, putative effector T cells (CD3+/CD4+/CD25medium/HLA-DR+ cells). We conclude some, but not all, schistosomiasis mansoni patients develop high percentages of circulating Treg, and effective treatment both decreases the levels of these cells and changes their phenotypes, possibly because of the removal of constant exposure to antigens from intravascular, egg-producing adult worms.
PMCID: PMC2602861  PMID: 17978070
5.  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
6.  Cytokine Control of the Granulomatous Response in Schistosoma mansoni-Infected Baboons: Role of Exposure and Treatment 
Infection and Immunity  1999;67(12):6565-6571.
Variations in exposure and treatment may contribute to heterogeneity in immunity and granuloma-induced pathology in human schistosomiasis. To examine this hypothesis, olive baboons were either repeatedly infected with Schistosoma mansoni cercariae or received an equivalent dose in a single infection. They were then cured with praziquantel and reinfected with a single exposure. Serial liver biopsies were obtained throughout the course of the experiment, and cytokine responses by peripheral blood mononuclear cells were measured every 2 to 3 weeks. Reinfection after treatment resulted in a twofold-smaller granuloma size at 6 and 9 weeks after infection compared to the size for the same period after primary infection (P < 0.001) but had no effect at 16 or 19 weeks postinfection. The pattern of exposure did not influence granuloma size. During primary infection schistosome-soluble egg antigen (SEA)-induced cytokine production correlated with granulomatous inflammation. Cytokine levels peaked during the acute infection, declined with chronic infection, and became undetectable after treatment. Reinfection after treatment stimulated a two- to three-fold increase in SEA-specific interleukin-4 (IL-4), IL-5, IL-10, IL-2, and transforming growth factor β (TGF-β) production and a marked rise in SEA-specific immunoglobulin E (IgE) and IgG regardless of the type of exposure. Cytokine production was significantly greater in repeatedly exposed animals (P < 0.001). SEA-induced gamma interferon production, however, did not increase with reinfection after treatment. SEA-induced TGF-β was the only cytokine that remained elevated as the infection become chronic and correlated with diminished hepatic granuloma size, implying its participation in down-modulation. These studies demonstrate that baboons partially retain their ability to down-modulate the granulomatous response after treatment.
PMCID: PMC97068  PMID: 10569776
7.  Utility of Repeated Praziquantel Dosing in the Treatment of Schistosomiasis in High-Risk Communities in Africa: A Systematic Review 
Background
Controversy persists about the optimal approach to drug-based control of schistosomiasis in high-risk communities. In a systematic review of published studies, we examined evidence for incremental benefits from repeated praziquantel dosing, given 2 to 8 weeks after an initial dose, in Schistosoma-endemic areas of Africa.
Methodology/Principal Findings
We performed systematic searches of electronic databases PubMed and EMBASE for relevant data using search terms ‘schistosomiasis’, ‘dosing’ and ‘praziquantel’ and hand searches of personal collections and bibliographies of recovered articles. In 10 reports meeting study criteria, improvements in parasitological treatment outcomes after two doses of praziquantel were greater for S. mansoni infection than for S. haematobium infection. Observed cure rates (positive to negative conversion in egg detection assays) were, for S. mansoni, 69–91% cure after two doses vs. 42–79% after one dose and, for S. haematobium, 46–99% cure after two doses vs. 37–93% after a single dose. Treatment benefits in terms of reduction in intensity (mean egg count) were also different for the two species—for S. mansoni, the 2-dose regimen yielded an weighted average 89% reduction in standardized egg counts compared to a 83% reduction after one dose; for S. haematobium, two doses gave a 93% reduction compared to a 94% reduction with a single dose. Cost-effectiveness analysis was performed based on Markov life path modeling.
Conclusions/Significance
Although schedules for repeated treatment with praziquantel require greater inputs in terms of direct costs and community participation, there are incremental benefits to this approach at an estimated cost of $153 (S. mansoni)–$211 (S. haematobium) per additional lifetime QALY gained by double treatment in school-based programs. More rapid reduction of infection-related disease may improve program adherence, and if, as an externality of the program, transmission can be reduced through more effective coverage, significant additional benefits are expected to accrue in the targeted communities.
Author Summary
Infection by Schistosoma worms causes serious disease among people who live in areas of Africa, South America, and Asia where these parasites are regularly transmitted. Although yearly treatment with the drug praziquantel is fairly effective in reducing or eliminating active infection, it does not cure everyone, and reinfection remains a continuing problem in high-risk communities. Studies have suggested that a repeat dose of praziquantel, given 2 to 8 weeks after the first dose, can improve cure rates and reduce remaining intensity of infections in population-based programs. Our systematic review of published research found that, on average, in Africa, such repeated dosing appears to offer particular advantages in the treatment of S. mansoni, the cause of intestinal schistosomiasis, but there was less consistent improvement after double-dosing for S. haematobium, the cause of urogenital schistosomiasis. Based on this evidence, we used a calibrated life-path model to predict the costs and benefits of a single-dose vs. a double-dose strategy in a typical high-risk community. Our projections suggest cost-effective incremental benefits from double dosing in terms of i) limiting a person's total years spent infected and ii) limiting the number of years they spend with heavy infection, with consequent improvements in quality of life.
doi:10.1371/journal.pntd.0001321
PMCID: PMC3176745  PMID: 21949893
8.  Schistosoma mansoni infection reduces the incidence of murine cerebral malaria 
Malaria Journal  2010;9:5.
Background
Plasmodium and Schistosoma are two of the most common parasites in sub-tropical areas. Deregulation of the immune response to Plasmodium falciparum, characterized by a Th1 response, leads to cerebral malaria (CM), while a Th2 response accompanies chronic schistosomiasis.
Methods
The development of CM was examined in mice with concomitant Schistosoma mansoni and Plasmodium berghei ANKA infections. The effect of S. mansoni egg antigen injection on disease development and survival was also determined. Cytokine serum levels were estimated using ELISA. Statistical analysis was performed using t-test.
Results
The results demonstrate that concomitant S. mansoni and P. berghei ANKA infection leads to a reduction in CM. This effect is dependent on infection schedule and infecting cercariae number, and is correlated with a Th2 response. Schistosomal egg antigen injection delays the death of Plasmodium-infected mice, indicating immune involvement.
Conclusions
This research supports previous claims of a protective effect of helminth infection on CM development. The presence of multiple parasitic infections in patients from endemic areas should therefore be carefully noted in clinical trials, and in the development of standard treatment protocols for malaria. Defined helminth antigens may be considered for alleviation of immunopathological symptoms.
doi:10.1186/1475-2875-9-5
PMCID: PMC2822789  PMID: 20051114
9.  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
10.  Schistosoma mansoni Antigens Modulate Experimental Allergic Asthma in a Murine Model: a Major Role for CD4+ CD25+ Foxp3+ T Cells Independent of Interleukin-10▿  
Infection and Immunity  2008;77(1):98-107.
In areas where schistosomiasis is endemic, a negative correlation is observed between atopy and helminth infection, associated with a low prevalence of asthma. We investigated whether Schistosoma mansoni infection or injection of parasite eggs can modulate airway allergic inflammation in mice, examining the mechanisms of such regulation. We infected BALB/c mice with 30 S. mansoni cercariae or intraperitoneally injected 2,500 schistosome eggs, and experimental asthma was induced by ovalbumin (OVA). The number of eosinophils in bronchoalveolar lavage fluid was higher in the asthmatic group than in asthmatic mice infected with S. mansoni or treated with parasite eggs. Reduced Th2 cytokine production, characterized by lower levels of interleukin-4 (IL-4), IL-5, and immunoglobulin E, was observed in both S. mansoni-treated groups compared to the asthmatic group. There was a reduction in the number of inflammatory cells in lungs of S. mansoni-infected and egg-treated mice, demonstrating that both S. mansoni infection and the egg treatment modulated the lung inflammatory response to OVA. Only allergic animals that were treated with parasite eggs had increased numbers of CD4+ CD25+ Foxp3+ T cells and increased levels of IL-10 and decreased production of CCL2, CCL3, and CCL5 in the lungs compared to the asthmatic group. Neutralization of IL-10 receptor or depletion of CD25+ T cells in vivo confirmed the critical role of CD4+ CD25+ Foxp3+ regulatory T cells in experimental asthma modulation independent of IL-10.
doi:10.1128/IAI.00783-07
PMCID: PMC2612239  PMID: 18824533
11.  Schistosomal egg granuloma-derived fibroblast-stimulating factor is apparently distinct from interleukin-1. 
Infection and Immunity  1989;57(3):679-684.
We have previously reported that egg granulomas isolated from livers of Schistosoma mansoni-infected euthymic mice in vitro elaborate a factor(s) that stimulates a variety of fibroblast responses including fibroblast proliferation and enhanced synthesis of extracellular matrix proteins. We have postulated that these factors play a role in the pathogenesis of hepatic fibrosis in schistosomiasis mansoni. Serum-free supernatants from egg granuloma cultures also stimulate thymocyte proliferation in an assay that defects interleukin-1 (IL-1). Thymocytes and fibroblasts are stimulated to proliferate by the same fractions of egg granuloma culture supernatant separated by gel filtration, isoelectric focusing, and ion-exchange chromatography. This suggested that granuloma-derived IL-1 is responsible for the observed fibroblast stimulation. Here we report that the ability of granuloma culture supernatants to stimulate the IL-1-sensitive D10.G4.1 cells but not fibroblasts is removed by treatment with immobilized anti-IL-1 antibody. We also observed that dialyzed culture supernatants from egg granulomas obtained from infected congenitally athymic (nude) mice also stimulate fibroblast proliferation. Treatment with anti-IL-1 antibody did not abrogate this response. In contrast to our experience with egg granulomas isolated from euthymic mice, IL-1- and fibroblast-stimulating activity could be separated by gel filtration and isoelectric focusing. We conclude that the fibroblast growth-stimulating activities elaborated by egg granulomas from S. mansoni-infected euthymic and athymic mice may be different but both appear to be distinct from IL-1.
PMCID: PMC313161  PMID: 2492969
12.  Effect of Chemotherapy with Praziquantel on the Production of Cytokines and Morbidity Associated with Schistosomiasis Mansoni▿  
The objective of the present study was to test the hypothesis that treatment of schistosomiasis mansoni with praziquantel can alter significantly the immune response of patients and generate a reversal of the level of fibrosis. Peripheral blood mononuclear cell (PBMC) samples were collected from, and abdominal ultrasound examinations conducted on, volunteers infected with Schistosoma mansoni and living in an area where the disease is endemic, both prior to and one year after treatment with praziquantel. Subjects were classified into groups according to the level of pathology (i.e., absent, incipient, moderate, or severe fibrosis). PBMCs were stimulated with schistosome soluble egg antigens (SEA), and the levels of production of the cytokines gamma interferon (IFN-γ), tumor necrosis factor alpha, transforming growth factor β, and interleukin-4 (IL-4), IL-10, and IL-13 were determined. The chemotherapy was effective in reducing morbidity, particularly for individuals presenting with severe fibrosis. When levels of cytokine production in posttreatment PBMC cultures stimulated by SEA were categorized as low or high, significant differences in the distribution of IL-13 levels between groups presenting with or not presenting with fibrosis were established. Comparison of pre- and posttreatment SEA-induced cytokine levels in individuals who had experienced no change in the grade of fibrosis following chemotherapy revealed that the level of IFN-γ decreased in subjects with fibrosis whereas that of IL-10 decreased in individuals with and without fibrosis. The data suggest that chemotherapy is effective in reducing the morbidity of the disease and that the level of IL-13 may be a useful indicator of the persistence of fibrosis following treatment.
doi:10.1128/AAC.00173-08
PMCID: PMC2493106  PMID: 18519730
13.  Neonatal Idiotypic Exposure Alters Subsequent Cytokine, Pathology, and Survival Patterns in Experimental Schistosoma mansoni Infections  
Exposure to maternal idiotypes (Ids) or antigens might predispose a child to develop an immunoregulated, asymptomatic clinical presentation of schistosomiasis. We have used an experimental murine system to address the role of Ids in this immunoregulation. Sera from mice with 8-wk Schistosoma mansoni infection, chronic (20-wk infection) moderate splenomegaly syndrome (MSS), or chronic hypersplenomegaly syndrome (HSS) were passed over an S. mansoni soluble egg antigen (SEA) immunoaffinity column to prepare Ids (8WkId, MSS Id, HSS Id). Newborn mice were injected with 8WkId, MSS Id, HSS Id, or normal mouse immunoglobulin (NoMoIgG) and infected with S. mansoni 8 wk later. Mice exposed to 8WkId or MSS Id as newborns had prolonged survival and decreased morbidity compared with mice that received HSS Id or NoMoIgG. When stimulated with SEA, 8WkId, or MSS Id, spleen cells from mice neonatally injected with 8WkId or MSS Id produced more interferon γ than spleen cells from mice neonatally injected with HSS Id or NoMoIgG. Furthermore, neonatal exposure to 8WkId or MSS Id, but not NoMoIgG or HSS Id, led to significantly smaller granuloma size and lower hepatic fibrosis levels in infected mice. Together, these results indicate that perinatal exposure to appropriate anti-SEA Ids induces long-term effects on survival, pathology, and immune response patterns in mice subsequently infected with S. mansoni.
PMCID: PMC2192931  PMID: 9989978
schistosomiasis; idiotypes; granuloma; splenomegaly; mice
14.  CD4+CD25+ Regulatory Cells Contribute to the Regulation of Colonic Th2 Granulomatous Pathology Caused by Schistosome Infection 
Eggs of the helminth Schistosoma mansoni accumulate in the colon following infection and generate Th2-biassed inflammatory granulomas which become down- modulated in size as the infection proceeds to chronicity. However, although CD4+CD25+FoxP3+regulatory T cells (Tregs) are known to suppress Th1-mediated colitis, it is not clear whether they control Th2 –associated pathologies of the large intestine which characterise several helminth infections. Here we used a novel 3D-multiphoton confocal microscopy approach to visualise and quantify changes in the size and composition of colonic granulomas at the acute and chronic phases of S. mansoni infection. We observed decreased granuloma size, as well as reductions in the abundance of DsRed+ T cells and collagen deposition at 14 weeks (chronic) compared to 8 weeks (acute) post-infection. Th2 cytokine production (i.e. IL-4, IL-5) in the colonic tissue and draining mesenteric lymph node (mLN) decreased during the chronic phase of infection, whilst levels of TGF-β1 increased, co-incident with reduced mLN proliferative responses, granuloma size and fibrosis. The proportion of CD4+CD25+FoxP3+Tregs: CD4+ cells in the mLN increased during chronic disease, while within colonic granulomas there was an approximate 4-fold increase. The proportion of CD4+CD25+FoxP3+Tregs in the mLN that were CD103+ and CCR5+ also increased indicating an enhanced potential to home to intestinal sites. CD4+CD25+ cells suppressed antigen-specific Th2 mLN cell proliferation in vitro, while their removal during chronic disease resulted in significantly larger granulomas, partial reversal of Th2 hypo-responsiveness and an increase in the number of eosinophils in colonic granulomas. Finally, transfer of schistosome infection-expanded CD4+CD25+Tregs down-modulated the development of colonic granulomas, including collagen deposition. Therefore, CD4+CD25+FoxP3+Tregs appear to control Th2 colonic granulomas during chronic infection, and are likely to play a role in containing pathology during intestinal schistosomiasis.
Author Summary
Schistosomiasis is an important parasitic helminth disease afflicting more than 200 million people worldwide. Infections are typically chronic and in the case of Schistosoma mansoni and S. japonicum the majority give rise to an intestinal form of disease caused by the deposition of parasite eggs in the colon and terminal ileum. The eggs cause Th2-associated inflammatory immune granulomas to form, which as the disease develops, are down-regulated by cells of the immune system. However, the mechanisms which underpin the down-regulation of granulomas in the large intestine are not known. In order to investigate the phenomenon of Th2-associated colonic inflammation, we utilized a murine model of infection with S. mansoni and compared immune responses at the acute and chronic phases of infection. We show that a type of regulatory T helper lymphocyte (CD4+CD25+FoxP3+Treg) contributes to regulation of colonic inflammation. These cells modulate anti-egg Th2 responses within the mesenteric lymph nodes and granulomatous pro-fibrotic Th2 responses within the colon. Our study highlights the importance of CD4+CD25+FoxP3+Tregs as a source of regulatory pressure on granuloma formation in the colon and by implication humans with chronic intestinal schistosomiasis.
doi:10.1371/journal.pntd.0001269
PMCID: PMC3153428  PMID: 21858239
15.  Performance and Safety of Praziquantel for Treatment of Intestinal Schistosomiasis in Infants and Preschool Children 
Background
In 2012 the WHO formally recognised that infants and preschool children are at significant risk of schistosomiasis and qualify for treatment with praziquantel (PZQ). Targeted surveys determining both the performance and safety of this drug are now needed in endemic areas. We have formally assessed parasitological cure and putative side-effects in a prospective cohort of Schistosoma mansoni-infected children (aged 5 months–7 years old) in lakeshore settings of Uganda.
Methodology/Principal Findings
From a total of 369 children found to be egg-patent for intestinal schistosomiasis, 305 were followed-up three to four weeks after PZQ treatment and infection status re-assessed. Separately, a previously tested side-effect questionnaire was employed before and 24 hours after PZQ treatment to assess incidence and amelioration of symptoms in young children and their mothers. While the overall observed parasitological cure was 56.4%, a significant difference was found between a sub-set of children who had a history of multiple PZQ treatments (between one and four in an 18 month period), where cure rate was 41.7%, and those who had never received treatment (cure rate was 77·6%). PZQ proved to be safe, with only mild reported side effects which cleared within a month after treatment. Prevalence of reported symptoms was significantly lower in children than in mothers, and fewer side-effects were reported upon subsequent rounds of PZQ treatment.
Conclusion/Significance
Our findings show that PZQ treatment of young children resulted in satisfactory cure rates, and marked reduction in egg-output, with only mild and transient reported side-effects. However, the cure rate is clearly lower in younger children and those with history of previous treatment. Cure rate, but not egg reduction rate, was also lower in children with heavier pre-intervention infection intensity. With chemotherapy now recommended as a long-term strategy for disease control in young children, research into optimising the periodicity of targeted treatment strategies is now crucial.
Author Summary
Although there is now extensive evidence for infection in preschool-aged children, and even a change in WHO guidelines endorsing treatment of this young age class in endemic areas, very little work has been published on the performance of praziquantel in children below the age of six. Previous work on praziquantel performance in preschool aged children focused on Schistosoma haematobium infections (urogenital schistosomiasis), with few observational studies published for S. mansoni infections (intestinal schistosomiasis). With a formalised protocol, we show that delivery of praziquantel to preschool-aged children living in endemic areas is safe and efficacious. However, this work has also shed light on dynamics never previously explored. History of previous treatment and age below three years proved to be determining factors for the outcome of treatment. This work provides firm evidence that in an endemic population certain young individuals were simply not cured (no egg or antigen cessation) after standard doses of praziquantel. This potential for non-cure should not go overlooked since exposure to drug without cure (either due to parasite or human factors) can lead to emergence and spread of resistance to praziquantel. Bearing in mind that praziquantel is the only commercially available drug against schistosomiasis, we recommend further research to understand these dynamics.
doi:10.1371/journal.pntd.0001864
PMCID: PMC3475660  PMID: 23094120
16.  Parasitological impact of 2-year preventive chemotherapy on schistosomiasis and soil-transmitted helminthiasis in Uganda 
BMC Medicine  2007;5:27.
Background
Schistosomiasis and soil-transmitted helminthiasis (STH) are among the neglected tropical diseases in Africa. A national control program for these diseases was initiated in Uganda during March 2003. Annual treatment with praziquantel and albendazole was given to schoolchildren in endemic areas and to adults in selected communities where local prevalence of Schistosoma mansoni in schoolchildren was high.
Methods
The impact of the treatment program was monitored through cohorts of schoolchildren and adults. Their infection status with S. mansoni and STH was determined by parasitological examinations at baseline and at annual follow-ups. The prevalence and intensity of S. mansoni and STH before and after treatment were analyzed.
Results
Two rounds of treatment significantly reduced the prevalence of S. mansoni infection in schoolchildren across three regions in the country from 33.4–49.3% to 9.7–29.6%, and intensity of infection from 105.7–386.8 eggs per gram of faeces (epg) to 11.6–84.1 epg. The prevalence of hookworm infection was reduced from 41.2–57.9% to 5.5–16.1%, and intensity of infection from 186.9–416.8 epg to 3.7–36.9 epg. The proportion of children with heavy S. mansoni infection was significantly reduced from 15% (95% CI 13.4–16.8%) to 2.3% (95% CI 1.6–3.0%). In adults, significant reduction in the prevalence and intensity of S. mansoni and hookworm infections was also observed. More importantly, the prevalence and intensity of both S. mansoni and hookworm infections in the cohorts of newly-recruited 6-year-olds who had never previously received treatment decreased significantly over 2 years: 34.9% (95% CI 31.9–37.8%) to 22.6% (95% CI 19.9–25.2%) and 171.1 epg (95% CI 141.5–200.7) to 72.0 epg (95% CI 50.9–93.1) for S. mansoni; and 48.4% (95% CI 45.4–51.5) to 15.9% (95% CI 13.6–18.2) and 232.7 epg (95% CI 188.4–276.9) to 51.4 epg (95% CI 33.4–69.5) for hookworms, suggesting a general decline in environmental transmission levels.
Conclusion
Annual anthelminthic treatment delivered to schoolchildren and to adults at high risk in Uganda can significantly reduce the prevalence and intensity of infection for schistosomiasis and STH, and potentially also significantly reduce levels of environmental transmission of infection.
doi:10.1186/1741-7015-5-27
PMCID: PMC2014753  PMID: 17767713
17.  Association of Schistosoma mansoni-Specific IgG and IgE Antibody Production and Clinical Schistosomiasis Status in a Rural Area of Minas Gerais, Brazil 
PLoS ONE  2014;9(2):e88042.
Background
Studies in murine models and human populations have indicated that the collagen-rich granulomatous response against parasite eggs trapped in the liver is associated with the development of severe hepatosplenic schistosomiasis, characterized by periportal fibrosis and portal hypertension. The role of the humoral response in parasite susceptibility has been well established, but its participation in disease severity remains poorly understood. In this work, we evaluated the relationship between parasite-reactive IgE and IgG levels and schistosomiasis morbidity in infected patients with similar parasite burdens.
Methodology/Principal Findings
Ninety-seven Schistosoma mansoni-infected individuals were subjected to clinical examination and abdominal ultrasound analysis. IgG reactivity and IgE concentration against Schistosoma mansoni soluble egg antigens (SEA) and adult worm antigen preparation (SWAP) were evaluated by ELISA assay. Multivariable linear regression models were used to evaluate the relationship between parasite-reactive antibodies and the co-variables investigated. The study population showed low parasite burden (median 30 eggs/g feces), constant re-infection, and signs of fibrosis was detected in more than 30% of individuals. Most infected individuals showed IgG reactivity, and the median concentrations of IgE anti-SEA and anti-SWAP antibodies were 1,870 and 1,375 ng/mL, respectively. There was no association between parasite burden and antibody response or any parameter of disease severity. However, IgG anti-SWAP level was positively associated with morbidity parameters, such as spleen size and thickness of portal vein at the entrance and secondary branch. In contrast, the data also revealed independent inverse correlations between concentration of parasite-reactive IgE and gallbladder wall thickness, a marker of fibrosis in schistosomiasis.
Conclusions/Significance
The data indicate that IgG anti-SWAP is positively associated with severe schistosomiasis, independently of parasite burden, while high production of parasite-specific IgE is associated with mild disease in the human population. Antibody profiles are good correlates for schistosomiasis severity and could be tested as biomarkers of disease severity.
doi:10.1371/journal.pone.0088042
PMCID: PMC3913716  PMID: 24505371
18.  Exposure to malaria affects the regression of hepatosplenomegaly after treatment for Schistosoma mansoni infection in Kenyan children 
BMC Medicine  2004;2:36.
Background
Schistosoma mansoni and malaria infections are often endemic in the same communities in sub-Saharan Africa, and both have pathological effects on the liver and the spleen. Hepatosplenomegaly associated with S. mansoni is exacerbated in children with relatively high exposure to malaria. Treatment with praziquantel reduces the degree of hepatosplenomegaly, but the condition does not completely resolve in some cases. The present analysis focused on the possibility that exposure to malaria infection may have limited the resolution of hepatosplenomegaly in a cohort of Kenyan schoolchildren.
Methods
Ninety-six children aged 6–16, from one community in Makueni district, Kenya, were treated with praziquantel. At baseline, all children had hepatomegaly and most had splenomegaly. The source of S. mansoni infection, a river, was molluscicided regularly over the following three years to limit S. mansoni re-infection, whereas malaria exposure was uninterrupted. Hepatic and splenic enlargement was assessed annually outside the malaria transmission season.
Results
Children living in an area of relatively high exposure to both infections presented with the largest spleens before treatment and at each follow-up. Spleens of firm consistency were associated with proximity to the river. The regression of hepatomegaly was also affected by location, being minimal in an area with relatively low S. mansoni exposure but high exposure to malaria, and maximal in an area with relatively low exposure to both infections.
Conclusions
The outcome of treating cases of hepatosplenomegaly with praziquantel in this cohort of Kenyan children depended strongly on their level of exposure to malaria infection. Furthermore, a residual burden of hepatosplenic morbidity was observed, which was possibly attributable to the level of exposure to malaria. The results suggest that exposure to malaria infection may be a significant factor affecting the outcome of praziquantel treatment to reduce the level of hepatosplenic morbidity.
doi:10.1186/1741-7015-2-36
PMCID: PMC522803  PMID: 15450118
19.  Mice lacking the gamma interferon receptor have an impaired granulomatous reaction to Schistosoma mansoni infection. 
Infection and Immunity  1997;65(8):3457-3461.
The egg-induced granulomatous reaction in Schistosoma mansoni-infected individuals develops within the portal system of the liver and is the major pathological finding in schistosomiasis. We have infected mice lacking the gamma interferon (IFN-gamma) receptor with S. mansoni larvae and studied the development of hepatic granulomas in these mutant mice in comparison to that in control wild-type mice. In the absence of IFN-gamma activity, a dramatic reduction in the size and architecture of the granuloma was observed. Granulomas from mutant mice were smaller than those from the control group and showed a significant reduction in the number of infiltrating inflammatory cells. Moreover, they appear to prematurely progress to the chronic phase of the reaction at a time when the control group still has acute inflammation. Our data suggests a pivotal role for IFN-gamma in the early events of the granulomatous reaction in vivo.
PMCID: PMC175489  PMID: 9234812
20.  Suppressive effect of interleukin-4 neutralization differs for granulomas around Schistosoma mansoni eggs injected into mice compared with those around eggs laid in infected mice. 
Infection and Immunity  1995;63(7):2532-2536.
The principal pathological manifestation of murine Schistosoma mansoni infection is the egg-induced granuloma. Synchronous pulmonary granulomas forming around intravenously injected schistosome eggs are widely used to study the immunopathology of schistosomiasis. A number of anticytokine antibody treatments have a remarkable effect in modulating granulomas in this model but little effect on the size of hepatic granulomas around laid eggs during experimental infection. To examine this discrepancy, we examined the effects of anticytokine antibodies on liver and lung granulomas around injected eggs and around eggs laid during infection in both locations. Anti-interleukin-4 (IL-4) treatment greatly reduced the volume of granulomas around eggs injected into the liver via the portal vein and around eggs injected into the lung via the tail vein. On the contrary, granulomas around eggs laid by worms in either the liver or the lung during the course of infection were not significantly decreased in size by anti-IL-4 treatment. Thus, site is not important for the disparate effects of anti-IL-4 in granuloma formation around injected versus laid eggs. This effect is seen in naive and sensitized animals and is most probably due to differences in the quality of injected eggs versus those laid in situ by the worms.
PMCID: PMC173338  PMID: 7790066
21.  Mechanism of Anemia in Schistosoma mansoni–Infected School Children in Western Kenya 
A better understanding of the mechanism of anemia associated with Schistosoma mansoni infection might provide useful information on how treatment programs are implemented to minimize schistosomiasis-associated morbidity and maximize treatment impact. We used a cross-sectional study with serum samples from 206 Kenyan school children to determine the mechanisms in S. mansoni-associated anemia. Serum ferritin and soluble transferrin receptor levels were measured by using an enzyme-linked immunosorbent assay. Results suggest that S. mansoni-infected persons are more likely (odds ratio = 3.68, 95% confidence interval = 1.33–10.1) to have levels of serum ferritin (> 100 ng/mL) that are associated with anemia of inflammation (AI) than S. mansoni-uninfected children. Our results suggest that AI is the most common form of anemia in S. mansoni infections. In contrast, the mechanism of anemia in S. mansoni-uninfected children was iron deficiency. Moreover, the prevalence of AI in the study participants demonstrated a significant trend with S. mansoni infection intensity (P < 0.001). Our results are consistent with those observed in S. japonicum-associated anemia.
doi:10.4269/ajtmh.2012.12-0248
PMCID: PMC3516261  PMID: 22987658
22.  Evidence that cytokine-mediated immune interactions induced by Schistosoma mansoni alter disease outcome in mice concurrently infected with Trichuris muris 
In murine models of Schistosoma mansoni infection, egg production is associated with a switch from T helper cell (Th)1- to Th2-type responses to both schistosome-specific and unrelated antigens. Polyparasitism is common in human populations within S. mansoni endemic areas. We have, therefore, examined whether coinfection with S. mansoni could affect the outcome of a second parasitic infection, through Th2 cytokine-dependent modifications to the host immune response. We find that when mice susceptible to infection with the gut nematode Trichuris muris are coinfected with S. mansoni, they acquire the capacity to resolve T. muris infection, thus demonstrating a resistant phenotype. This ability to expel T. muris is associated with the production of Th2- associated cytokines, and corresponding antibody isotypes, in response to S. mansoni egg antigens. The Th2 response shows that there is no compartmentalization between spleen and mesenteric lymph nodes, and that the expulsion of T. muris is not caused by any changes in the host intestine associated with excretion of schistosome eggs. This influence of schistosome infections may be important, not only for the outcome of infections with unrelated pathogens in endemic areas, but also for the efficacy of vaccines in such areas.
PMCID: PMC2191884  PMID: 7836929
23.  Role of Host Granulomatous Response in Murine Schistosomiasis Mansoni 
Journal of Clinical Investigation  1980;66(6):1191-1199.
Eosinophils form 50% of cells in the host granulomatous response to Schistosoma mansoni eggs, but their functional role in these granulomas and their relation to egg destruction is unknown. We have studied the course of S. mansoni infection in mice treated with normal rabbit serum (NRS) or depleted of their eosinophils by monospecific anti-eosinophil serum (AES). At 6-wk of infection (after 2 wk of egg deposition) the AES-treated animals were similar to NRS-treated controls with the exception that hepatic granulomas in the AES-treated animals were 50% smaller and devoid of eosinophils. At 8 wk of infection, AES-treated mice had significantly higher mortality, spleen weight, portal pressure, and 80% more eggs retained in their livers. These data suggest that eosinophil depletion delayed egg destruction. We subsequently studied destruction of eggs injected into the pulmonary microvasculature of sensitized mice. 2,000 S. mansoni eggs were intravenously injected into the tail veins of mice treated with NRS, anti-neutrophil serum, AES or ATG (anti-thymocyte globulin); at time intervals the remaining eggs were recovered from the lungs by tissue digestion. Egg recovery from NRS- or anti-neutrophil serum-treated mice began to decrease by day 16 and the percent recovery of eggs at day 24 was 55 and 52%, respectively. In contrast, animals treated with AES had smaller lung granulomas that were devoid of eosinophils and a marked delay of egg destruction was seen. It took until day 44 for 50% of the eggs to be destroyed. In ATG-treated animals smaller granulomas were seen that had diminished lymphocytes and also 75% less eosinophils. ATG treatment apparently slowed egg destruction but was not statistically significant. Our data define the role of the eosinophils in destruction of schistosome eggs in vivo and delineates the protective function of these cells within the host granulomatous response.
PMCID: PMC371603  PMID: 7440710
24.  Schistosomal colonic disease. 
Gut  1990;31(4):439-442.
This study evaluates 216 patients with schistosomal colonic disease, diagnosed by endoscopic biopsies at the Armed Forces Hospital, Riyadh. The colonoscopic appearance was suggestive of schistosomiasis in 98 of these patients (45.37%), Schistosoma mansoni ova in stool was detected in only 24 of these 216 patients (11.11%). The most common histopathological finding in colonic biopsies of these patients was Schistosoma mansoni ova in the colonic mucosa with no or mild inflammatory cells infiltrates. These findings correlate with the endoscopic appearances in most patients. The most common symptoms were abdominal pain or distention in 84 patients (38.88%). Sixty five patients (30.09%) had hepatosplenic schistosomiasis. Eight patients had schistosomal polyps and two patients had colonic malignancy in which no association between their malignancy and Schistosoma mansoni infection was established. After antischistosomal treatment follow up, sigmoidoscopy was normal in 28 patients who previously had abnormal endoscopic appearances. Colonoscopic examination is valuable in colonic schistosomiasis as it can show characteristic colonic lesions and colonic biopsies are diagnostic and correlates with histological findings.
Images
PMCID: PMC1378420  PMID: 2110925
25.  Production of interferon-gamma by natural killer cells and aging in chronic human schistosomiasis. 
Mediators of Inflammation  2004;13(5-6):327-333.
BACKGROUND: Aging is associated with several alterations in the phenotype, repertoire and activation status of lymphocytes as well as in the cytokine profile produced by these cells. As a lifelong condition, chronic parasitic diseases such as human schistosomiasis overlaps with the aging process and no systematic study has yet addressed the changes in immune response during infection with Schistosoma mansoni in older individuals. AIM: Herein we study the influence of immunological alterations brought about by senescence in the course of schistosomiasis. MATERIALS AND METHODS: Individuals 10-95 years of age, from both sexes, from an endemic area for S. mansoni infection were matched by intensity of infection as measured by egg counts. We analyzed, as a parameter, cytokine expression by lymphocytes and natural killer cells after in vitro stimulation with soluble egg antigen and soluble worm antigen using flow cytometry. RESULTS: We demonstrated that the frequency of CD16+ interferon-gamma (IFN-gamma)+ natural killer cells in negative individuals over the age of 70 years is significantly higher than in positive individuals after in vitro stimulation with S. mansoni antigen extracts. The frequency of these cells is increased in all individuals over the age of 50 years and only declines in positive individuals after 70 years of age. Analysis of either CD4? or CD8? cells after antigen stimulation show no significant increase in frequency of IFN-gamma in negative or in positive individuals of this age group, suggesting that the effect on CD16+ cells is not T-cell dependent. CONCLUSION: Since production of IFN-gamma has been related to resistance to schistosome infection, our data suggest that age-associated changes in CD16+ cells may play a role in controlling infection intensity in the elderly in S. mansoni endemic areas of Brazil.
doi:10.1155/S0962935104000481
PMCID: PMC1781577  PMID: 15770048

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