Functional Polymorphisms in IL13 Are Protective against High Schistosoma mansoni Infection Intensity in a Brazilian Population

Audrey V Grant,Peisong Gao,Alvaro A Cruz,Kathleen C Barnes,Terri H Beaty,Maria Ilma Araujo,Eduardo Vieira Ponte,Ricardo Riccio Oliveira

doi:10.1371/journal.pone.0035863

Abstract

BackgroundIL-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.Methodology/Principal FindingsTwo 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).Conclusions/SignificanceThe 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.

Highlights

The worldwide prevalence of schistosomiasis is high at 200 million infected individuals, creating a substantial public health burden. [1] Schistosomiasis occurs in areas where humans come into contact with water harboring the intermediate snail host for Schistosoma mansoni in parts of South America, Africa and the Middle East; S. haematobium in Africa and the Middle East; or S. japonicum in China, South-East Asia and the Philippines. [1] Infection occurs when cercariae burrow directly through the skin, maturing into the adult form in the portal vasculature
The cytokine IL-13 is involved in immunoglobulin class switching to immunoglobulin E (IgE) and in airway hypersensitivity, mucus hypersecretion, and inflammation of the bowel. [6,7] IgE production is thought to have evolved as a protective feature in host defense against helminthes [2], but total serum IgE levels have been widely studied as a surrogate endophenotype relating to atopic disease [8], it is seldom studied in the context of helminthic infection
Genetic associations observed for functional polymorphisms, rs1800925 and rs20541, which are protective against high S. mansoni egg counts in our Brazilian study population, support evidence for a protective effect against high infection intensity for alleles associated with atopic disease, and as previously observed in a population endemic for the S. haematobium species of schistosomes

Summary

Introduction

The worldwide prevalence of schistosomiasis is high at 200 million infected individuals, creating a substantial public health burden. [1] Schistosomiasis occurs in areas where humans come into contact with water harboring the intermediate snail host for Schistosoma mansoni in parts of South America, Africa and the Middle East; S. haematobium in Africa and the Middle East; or S. japonicum in China, South-East Asia and the Philippines. [1] Infection occurs when cercariae burrow directly through the skin, maturing into the adult form in the portal vasculature. [1] These obstacles have motivated research to better understand schistosomiasis host immunity to identify those individuals susceptible to greatest intensity of infection for targeted treatment and prevention. Host immune response to infection involves differentiation of helper T cells into two major subtypes known as TH1 and TH2 cells. While TH1 cells elicit cellular immunity against intracellular bacteria and viruses, infection by helminths (including S. mansoni) induces a TH2 humoral response, accompanied by release of the cytokines IL-4, IL-5 and IL-13. [2,5] Activation of TH2 immunity underlies atopic diseases, including asthma, in response to stimulation by innocuous allergens. 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

Methods

Results

Conclusion