Characterization of the Schistosoma transcriptome opens up the world of helminth genomics

Among the metazoan parasites that cause debilitating disease in man, schistosomes are the first group for which near-complete transcriptome complements have been described. This new genomic information will have an enormous impact on all future investigations into the biology, pathogenesis and control of schistosomiasis

Identification of Schistosoma mansoni gender-associated gene transcripts by cDNA microarray profiling.

BACKGROUND: Parasitic helminths of the genus Schistosoma mate, achieve sexual maturity and produce eggs in the bloodstream of their definitive hosts, and the most important pathological consequences of the infection are associated with this process. We have used cDNA microarray technology to initiate genome-wide gene-expression studies of sex and sexual development in mature Schistosoma mansoni parasites. RESULTS: An S. mansoni-specific cDNA microarray was fabricated using 576 expressed sequence tags selected from three cDNA libraries and originating from two different parasite developmental stages. Five independent cDNA microarray hybridizations were analyzed using stringent filtering criteria and careful quality control, leading to the identification of 12 new female-associated and 4 new male-associated gene transcripts in the mature adult schistosome. Statistical analysis of variation demonstrated high levels of agreement within a cDNA microarray (correlation coefficient 0.91; median coefficient of variation 11.1%) and between cDNA microarrays (correlation coefficient 0.90; median coefficient of variation 14.4%). RT-PCR analysis confirmed the cDNA microarray results, thereby supporting the reliability of the system. CONCLUSIONS: Our study expands the list of S. mansoni gender-associated gene transcripts from all previous studies by a factor of two. Among the new associations identified, a tyrosinase ortholog was preferentially expressed in the adult female, and a dynein light-chain ortholog was highly induced in the adult male. cDNA microarrays offer the potential for exponential leaps in the understanding of parasite biology and this study shows how molecules involved in sexual biology can be rapidly identified.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Comparative biochemical analysis of three members of the Schistosoma mansoni TAL family: Differences in ion and drug binding properties.

The tegumental allergen-like (TAL) proteins from Schistosoma mansoni are part of a family of calcium binding proteins found only in parasitic flatworms. These proteins have attracted interest as potential drug or vaccine targets, yet comparatively little is known about their biochemistry. Here, we compared the biochemical properties of three members of this family: SmTAL1 (Sm22.6), SmTAL2 (Sm21.7) and SmTAL3 (Sm20.8). Molecular modelling suggested that, despite similarities in domain organisation, there are differences in the three proteins' structures. SmTAL1 was predicted to have two functional calcium binding sites and SmTAL2 was predicted to have one. Despite the presence of two EF-hand-like structures in SmTAL3, neither was predicted to be functional. These predictions were confirmed by native gel electrophoresis, intrinsic fluorescence and differential scanning fluorimetry: both SmTAL1 and SmTAL2 are able to bind calcium ions reversibly, but SmTAL3 is not. SmTAL1 is also able to interact with manganese, strontium, iron(II) and nickel ions. SmTAL2 has a different ion binding profile interacting with cadmium, manganese, magnesium, strontium and barium ions in addition to calcium. All three proteins form dimers and, in contrast to some Fasciola hepatica proteins from the same family; dimerization is not affected by calcium ions. SmTAL1 interacts with the anti-schistosomal drug praziquantel and the calmodulin antagonists trifluoperazine, chlorpromazine and W7. SmTAL2 interacts only with W7. SmTAL3 interacts with the aforementioned calmodulin antagonists and thiamylal, but not praziquantel. Overall, these data suggest that the proteins have different biochemical properties and thus, most likely, different in vivo functions

IgE-tailpiece associates with α-1-antitrypsin (A1AT) to protect IgE from proteolysis without compromising its ability to interact with FcεRI

Several splice variants of IgE exist in human plasma, including a variant called IgE-tailpiece (IgE-tp) that differs from classical IgE by the replacement of two carboxy-terminal amino acids with eight novel residues that include an ultimate cysteine. To date, the role of the secreted IgE-tp isoform in human immunity is unknown. We show that levels of IgE-tp are raised in helminth-infected donors, and that both the classical form of IgE (IgE-c) and IgE-tp interact with polymers of the serine protease inhibitor alpha-1-antitrypsin (A1AT). The association of IgE-tp with A1AT polymers in plasma protects the antibody from serine protease-mediated degradation, without affecting the functional interaction of IgE-tp with important receptors, including FcεR1. That polymers of A1AT protect IgE from degradation by helminth proteases may explain why these common and normally non-disease causing polymorphic variants of A1AT have been retained by natural selection. The observation that IgE can be complexed with polymeric forms of A1AT may therefore have important consequences for our understanding of the pathophysiology of pulmonary diseases that arise either as a consequence of A1AT-deficiency or through IgE-mediated type 1 hypersensitivity responses

Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on immune responses to schistosome antigens among the offspring: results of a randomised, placebo-controlled trial.

BACKGROUND: Offspring of women with schistosomiasis may exhibit immune responsiveness to schistosomes due to in utero sensitisation or trans-placental transfer of antibodies. Praziquantel treatment during pregnancy boosts maternal immune responses to schistosome antigens and reduces worm burden. Effects of praziquantel treatment during pregnancy on responses among offspring are unknown. METHODS: In a trial of anthelminthic treatment during pregnancy in Uganda (ISRCTN32849447; http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women with Schistosoma mansoni were examined for cytokine and antibody responses to schistosome worm (SWA) and egg (SEA) antigen, in cord blood and at age one year. Relationships to maternal responses and pre-treatment infection intensities were examined, and responses were compared between the offspring of women who did, or did not receive praziquantel treatment during pregnancy. RESULTS: Of 388 S. mansoni-infected women studied, samples were obtained at age one year from 215 of their infants. Stool examination for S. mansoni eggs was negative for all infants. Cord and infant samples were characterised by very low cytokine production in response to schistosome antigens with the exception of cord IL-10 responses, which were substantial. Cord and infant cytokine responses showed no association with maternal responses. As expected, cord blood levels of immunoglobulin (Ig) G to SWA and SEA were high and correlated with maternal antibodies. However, by age one year IgG levels had waned and were hardly detectable. Praziquantel treatment during pregnancy showed no effect on cytokine responses or antibodies levels to SWA or SEA either in cord blood or at age one year, except for IgG1 to SWA, which was elevated in infants of treated mothers, reflecting maternal levels. There was some evidence that maternal infection intensity was positively associated with cord blood IL-5 and IL-13 responses to SWA, and IL-5 responses to SEA, and that this association was modified by treatment with praziquantel. CONCLUSIONS: Despite strong effects on maternal infection intensity and maternal immune responses, praziquantel treatment of infected women during pregnancy had no effect on anti-schistosome immune responses among offspring by age one year. Whether the treatment will impact upon the offspring's responses on exposure to primary schistosome infection remains to be elucidated. TRIAL REGISTRATION: ISRCTN: ISRCTN32849447

Comparison of HIV-1 viral loads, CD4-Th2-lymphocytes and effects of praziquantel treatment among adults infected or uninfected with Schistosoma mansoni in fishing villages of north-western Tanzania

 Background: It is hypothesised that Th2 immunological environment associated with Schistosoma mansoni infection might favour replication of HIV-1 in co-infected individuals, results in increased viral loads. On the other hand, deworming using praziquantel might result in reduction of HIV-1 viral loads and increased CD4+ cell counts. This study was therefore, carried out to compare HIV -1 plasma loads, CD4-Th2-lymphocytes and the effects of praziquantel treatment on HIV-1 plasma loads and CD4+ cell counts among HIV-1 seropositive individuals infected or uninfected with S. mansoni.Methodology: A 9-month prospective longitudinal study was conducted among HIV-1 infected individuals aged 21-55 years with CD4+ cell counts ≥ 350cells/µL in fishing villages of North-Western Tanzania. Single stool samples were examined for S. mansoni eggs using Kato Katz technique at 6-month follow-up and 12 weeks after treatment. Venous blood samples were collected at baseline, at three and six-month follow-up and 12 weeks after praziquantel treatment for HIV-1 plasma viral loads and CD4+ cell quantification.Results: Of the 50 HIV-1 infected participants at baseline, 44% (22/50, 95%CI; 30.58-58.35) were found to be co-infected with S. mansoni at 6-month follow-up with a mean of 93.26GM-epg (95%CI: 60.42-143.95). The median CD4+ cell counts did not differ significantly between individuals infected with HIV-1 and those co-infected with HIV-1 and S. mansoni at baseline (P=0.62), 3-month (P=0.64) and 6-month (P=0.41) follow-up. Monthly decrease in CD4+ cells did not differ significantly between the two groups at all follow-up points (-30.39cell/µL versus -31.35cells/µL, P=0.89). Those infected with S. mansoni had a significantly higher mean log10 HIV-1 plasma viral load at baseline (5.98 ± 3.06 versus 9.21 ± 1.91copies/ml, P<0.0001) and 3-month follow-up (8.19 ± 2.17 versus 9.44 ± 1.99copies/ml, P<0.042) compared to those infected with HIV-1 only. This difference was not evident at the time of S. mansoni diagnosis at 6-month time point. Praziquantel treatment in co-infected individuals (n=12) did not result in any change in CD4+ cell counts and mean HIV-1 plasma viral loads (t=-0.9156, P=0.38), comparing baseline and 3-month follow-up after treatment. No correlation was observed between log S. mansoni egg counts and log10 HIV-1 RNA viral loads (r=-0.066, P=0.77) at six-month follow-up in co-infected individuals (n=22).Conclusion: HIV-1 plasma viral loads varied significantly among mono and co-infected individuals at baseline and 3-month follow-up. However, CD4+ cell counts did not vary between the two groups at all follow-up time points. Praziquantel treatment of co-infected individuals did not result in changes in CD4+ cell counts and HIV-1 plasma viral loads

Immune Modulation by Schistosoma mansoni Antigens in NOD Mice: Effects on Both Innate and Adaptive Immune Systems

We have shown that Schistosoma mansoni egg soluble antigen (SEA) prevents diabetes in the nonobese diabetic (NOD) mouse inducing functional changes in antigen presenting cells (APCs) and expanding T helper (Th) 2 and regulatory T cell (Treg) responses. A Th2 response to S. mansoni infection or its antigens is key to both the establishment of tolerance and successfully reproduction in the host. More recently we demonstrated that SEA treatment upregulates bioactive TGFβ on T cells with consequent expansion of Foxp3+ Tregs, and these cells might be important in SEA-mediated diabetes prevention together with Th2 cells. In this study we profile further the phenotypic changes that SEA induces on APCs, with particular attention to cytokine expression and markers of macrophage alternative activation. Our studies suggest that TGFβ from T cells is important not just for Treg expansion but also for the successful Th2 response to SEA, and therefore, for diabetes prevention in the NOD mouse