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Functional polymorphisms in IL13 are protective against high Schistosoma mansoni infection intensity in a Brazilian population.

ABSTRACT: IL-13 is a signature cytokine of the helper T cell type 2 (TH2) pathway which underlies host defense to helminthic infection and activates production of IgE in both parasitized populations and in urban settings after allergen exposure.Two functional polymorphisms in IL13, rs1800925 (or c.1-1111C>T) and rs20541 (or R130Q) were previously found to be associated with Schistosoma hematobium infection intensity. They have not been thoroughly explored in S. mansoni-endemic populations, however, and were selected along with 5 tagging SNPs for genotyping in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area of Conde, Bahia, in Brazil. Regression models using GEE to account for family membership and family-based quantitative transmission disequilibrium tests (QTDT) were used to evaluate associations with total serum IgE (tIgE) levels and S. mansoni fecal egg counts adjusted for non-genetic covariates. We identified a protective effect for the T allele at rs20541 (P?=?0.005) against high S. mansoni egg counts, corroborated by QTDT (P?=?0.014). Our findings also suggested evidence for protective effects for the T allele at rs1800925 and A allele at rs2066960 after GEE analysis only (P?=?0.050, 0.0002).The two functional variants in IL13 are protective against high S. mansoni egg counts. These markers showed no evidence of association with tIgE levels, unlike tIgE levels previously studied in non-parasitized or atopic study populations.

SUBMITTER: Grant AV

PROVIDER: S-EPMC3345031 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Functional polymorphisms in IL13 are protective against high Schistosoma mansoni infection intensity in a Brazilian population.

Grant Audrey V AV Araujo Maria Ilma MI Ponte Eduardo Vieira EV Oliveira Ricardo Riccio RR Gao Peisong P Cruz Alvaro A AA Barnes Kathleen C KC Beaty Terri H TH

PloS one 20120504 5

<h4>Background</h4>IL-13 is a signature cytokine of the helper T cell type 2 (TH2) pathway which underlies host defense to helminthic infection and activates production of IgE in both parasitized populations and in urban settings after allergen exposure.<h4>Methodology/principal findings</h4>Two functional polymorphisms in IL13, rs1800925 (or c.1-1111C>T) and rs20541 (or R130Q) were previously found to be associated with Schistosoma hematobium infection intensity. They have not been thoroughly e ...[more]

PMID: 22574126

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Project description:BackgroundSchistosomiasis 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 findingsIn 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-? and TNF-? 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/significanceOur 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.

Project description:BackgroundSchistosomiasis is a disease of major public health importance in sub-Saharan Africa. Immunoregulation begins early in schistosome infection and is characterized by hyporesponsiveness to parasite and bystander antigens, suggesting that a schistosome infection at the time of immunization could negatively impact the induction of protective vaccine responses. This study examined whether having a Schistosoma mansoni infection at the time of immunization with hepatitis B and tetanus toxoid (TT) vaccines impacts an individual's ability to achieve and maintain protective antibody levels against hepatitis B surface antigen or TT.MethodsAdults were recruited from Kisumu Polytechnic College in Western Kenya. At enrollment, participants were screened for schistosomiasis and soil transmitted helminths (STHs) and assigned to groups based on helminth status. The vaccines were then administered and helminth infections treated a week after the first hepatitis B boost. Over an 8 month period, 3 blood specimens were obtained for the evaluation of humoral and cytokine responses to the vaccine antigens and for immunophenotyping.Results146 individuals were available for final analysis and 26% were S. mansoni positive (Sm+). Schistosomiasis did not impede the generation of initial minimum protective antibody levels to either hepatitis B or TT vaccines. However, median hepatitis B surface antibody levels were significantly lower in the Sm+ group after the first boost and remained lower, but not significantly lower, following praziquantel (PZQ) treatment and final boost. In addition, 8 months following TT boost and 7 months following PZQ treatment, Sm+ individuals were more likely to have anti-TT antibody levels fall below levels considered optimal for long term protection. IL-5 levels in response to in vitro TT stimulation of whole blood were significantly higher in the Sm+ group at the 8 month time period as well.ConclusionsIndividuals with schistosomiasis at the start the immunizations were capable of responding appropriately to the vaccines as measured by antibody responses. However, they may be at risk of a more rapid decline in antibody levels over time, suggesting that treating schistosome infections with praziquantel before immunizations could be beneficial. The timing of the treatment as well as its full impact on the maintenance of antibodies against vaccine antigens remains to be elucidated.

Project description:BackgroundSchistosomiasis remains a major public health issue with over 90% of the prevalence rates recorded in Sub-Saharan Africa. In this study, the relationships between different interleukin gene polymorphisms (IL-13-591A/G, IL-13-1055C/T, IL-13-1258A/G) and Schistosoma haematobium infection levels were evaluated; as well as the host plasma antibodies and cytokine profiles associated with schistosomiasis infection.MethodologyA total of 469 school children aged 6 to 19 years from four schistosomiasis-endemic communities in Ghana were involved. Single urine and stool samples were obtained from each pupil, processed via sedimentation and Kato-Katz, and examined via microscopy for Schistosoma and soil-transmitted helminth (STH) eggs. Next, venous blood samples were drawn from 350 healthy pupils, and used to measure antibody and plasma cytokine levels by ELISA. Single nucleotide polymorphisms in the IL-13 gene were genotyped on 71 selected blood samples using the Mass Array technique.Principal findings and conclusionThe overall prevalence of urinary schistosomiasis was 21.11%. Community-level prevalences were 17.12%, 32.11%, 20.80%, and 15.32% for Asempaneye, Barikumah, Eyan Akotoguah, and Apewosika respectively. Generally, higher S. haematobium infection prevalence and intensity were recorded for participants with genotypes bearing the IL13-1055C allele, the IL13-591A, and the IL13-1258A alleles. Also, higher S. haematobium infection prevalence was observed among participants in the 12-14-year age group with the IL13-1055C, IL13-591A, and IL13-1258A alleles. Interestingly, higher STH prevalence was also observed among participants with the IL13-1055C, IL13-591A, and IL13-1258A alleles. Furthermore, the age-associated trends of measured antibodies and cytokines of S. haematobium-infected school-children depicted a more pro-inflammatory immune profile for pupils aged up to 1l years, and an increasingly anti-inflammatory profile for pupils aged 12 years and above. This work provides insight into the influence of IL-13 gene polymorphisms on S. haematobium, and STH infections, in school-aged children (SAC).

Project description:BackgroundSchistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases.Methodology/principal findingsWhile adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54-65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70-76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine.Conclusions/significanceGut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase-based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans.

Dataset Information

Functional polymorphisms in IL13 are protective against high Schistosoma mansoni infection intensity in a Brazilian population.

Publications

Functional polymorphisms in IL13 are protective against high Schistosoma mansoni infection intensity in a Brazilian population.

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