Abstract
Genetic and epigenetic factors are considered to be critical for host-parasite interactions. There are limited data on the role of such factors during human infections with Ascaris lumbricoides. Here, we describe the potential role of genetic factors as determinants of the Th2 immune response to A. lumbricoides in Brazilian children. Stool samples were collected from the children to detect A. lumbricoides by microscopy and peripheral blood leukocytes (PBLs) were cultured in whole blood cultures for detection of cytokines (IL-5, IL-10, and IL-13) in vitro. Levels of anti-A. lumbricoides IgE and IgG4 were measured in plasma. DNA was extracted from PBLs and genotyped using Illumina 2.5 Human Omni Beadchip. Candidate genes associated with A. lumbricoides responses were identified and SNVs in these selected genes associated with the Th2 immune response to A. lumbricoides. Haplotype, gene expression, and epigenetic analyses were done to identify potential associations with Th2 immune responses. GWAS on samples from 1,189 children identified WSB1 as a candidate gene, and IL-21R was selected as a biologically relevant linked gene for further analysis. Variants in WSB1 and IL21R were associated with markers of Th2 immune responses: increased A. lumbricoides-specific IgE and IL-5/IL-13 by PBLs from infected compared to uninfected individuals. In infected children, WSB1 but not IL21R gene expression was suppressed and increased methylation was observed in the WSB1 promoter region. This is the first study to show an association between genetic variants in WSB1 and IL21R and Th2 immune responses during A. lumbricoides infections in children. WSB1/IL21R pathways could provide a potential target for the treatment of Th2-mediated diseases.
Highlights
A quarter of the world’s population is estimated to be infected with soil-transmitted helminth (STH) parasites
The Manhattan plot for the genome wide analysis of single nucleotide variants (SNVs) associated with anti-A. lumbricoides IgE/IgG4 are shown in Figure 1 and the top 20 SNVs identified are listed in Table 2 with results of a mapping analysis for these provided in Supplementary Table 1
Previous studies suggest that the balance between helminth specific IgE and IgG4 might determine resistance or susceptibility to helminth infections, showing that levels of specific IgE have been correlated with resistance to infection, whereas levels of IgG4 have been associated with susceptibility [34,35,36]
Summary
A quarter of the world’s population is estimated to be infected with soil-transmitted helminth (STH) parasites. Among STH infections, Ascaris lumbricoides infection is estimated to infect 820 millions causing a significant burden of morbidity and mortality, the latter generally being associated with intestinal obstruction [3,4,5]. Among those with high parasite burdens, can impair host nutrition leading to growth stunting and diminished cognitive development [1, 6]. Ascaris lumbricoides infection induces strong Th2-type immune responses in infected humans leading to the production of high circulating levels of total and parasite-specific IgE, generally targeted at larvae that undergo a phase of extraintestinal migration through the lungs. Th2-induced host protective mechanisms against A. lumbricoides parasites include eosinophil-mediated killing of larvae in the tissues, mast-cell degranulation in the tissues and intestinal tract, and increased intestinal mucus production through goblet-cell hyperplasia [7, 8]
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