Association of Antibodies to Helminth Defense Molecule 1 With Inflammation, Organomegaly, and Decreased Nutritional Status in Schistosomiasis Japonica

Abstract

Immunomodulation enhances parasite fitness by reducing inflammation-induced morbidity in the mammalian host, as well as by attenuating parasite-targeting immune responses. Using a whole-proteome differential screening method, we identified Schistosoma japonicum helminth defense molecule 1 (SjHDM-1) as a target of antibodies expressed by S. japonicum-resistant but not S. japonicum-susceptible individuals. In a longitudinal cohort study (n = 644) conducted in a S. japonicum-endemic region of the Philippines, antibody levels to SjHDM-1 did not predict resistance to reinfection but were associated with increased measures of inflammation. Individuals with high levels of anti-SjHDM-1 immunoglobulin G had higher levels of C-reactive protein than those with low anti-SjHDM-1. High anti-SjHDM-1 immunoglobulin G responses were also associated with reduced biomarkers of nutritional status (albumin), as well as decreased anthropometric measures of nutritional status (weight-for-age and height-for-age z scores) and increased measures of hepatomegaly. Our results suggest that anti-SjHDM-1 responses inhibit the immunomodulatory function of SjHDM-1, resulting in increased morbidity rates.

Keywords: Schistosoma japonicum; helminth defense molecule; inflammation; malnutrition; organomegaly.

Figure 1.

Vaccination with recombinant Schistosoma japonicum HDM 1 (rSjHDM-1) is not associated with reduction of worm burden in mice, and anti–Schistosoma japonicum helminth defense molecule 1 SjHDM-1 immunoglobulin (Ig) G is not associated with protection in humans. A, Worm burden, shown as number of worms recovered at perfusion from rSjHDM-1–TiterMax–vaccinated mice (n = 9) and control mice (n = 9). Bars represent means; error bars, standard deviations. rSjHDM-1–TiterMax–vaccinated and control groups were compared using unpaired Student t tests. B, S. japonicum infection intensity (as represented by eggs per gram of stool [EPG]) by tertile of the distribution of anti–SjHDM-1 IgG antibody levels in cohort II (n = 194). Bars represent mean S. japonicum egg counts per tertile; error bars, standard deviations. C, Anti–SjHDM-1 IgG antibody abundance of the individuals comprising the resistant (n = 10) and susceptible (n = 10) groups (human cohort II) used to screen S. japonicum adult worm complementary DNA library, as measured using bead-based assay. Bars represent means; error bars, standard deviations. Comparison of resistant and susceptible groups were compared using unpaired Student t test. Abbreviation: NS, not significant.

Figure 2.

Profile of antigen-specific immunoglobulin (Ig) G levels in cohort I. Antigen-specific IgG antibody abundance for 13 Schistosoma japonicum antigens, as measured by bead-based assay, in cohort I (n = 644) at baseline. Box plots represent interquartile ranges of antibody abundances, with individual quantifications of antibody abundance per participant represented as individual dots. Whiskers represent the range of data points, from minimum to maximum. Abbreviations: SEA, soluble egg antigen; Sj41, Sj68, Sj97, and Sj191, S. japonicum 41, 68, 97, and 191; SjALDFla, S. japonicum aldolase; SjERBP1a, S. japonicum plasminogen activator inhibitor 1 RNA-binding protein 1a; SjERBP1b, S. japonicum plasminogen activator inhibitor 1 RNA-binding protein 1b; SjF1a, S. japonicum ferritin-1 heavy chain; SjF2, S. japonicum ferritin-1 light chain; SjG10, also known as S. japonicum CHGC04682; SjHDM-1, S. japonicum helminth defense molecule 1; SWAP, soluble worm antigen preparation.

Figure 3.

Schistosoma japonicum helminth defense molecule 1 (SjHDM-1) is a component of the excretory/secretory products of adult S. japonicum worm culture. Western blot analysis was used to identify an approximately 11-kDa protein in 24-hour culture of S. japonicum adult worms perfused from infected mice. Lane 1, culture medium; lane 2, culture medium spiked with 1.0 μg of mouse monoclonal immunoglobulin (Ig) G₁; lane 3, culture medium spiked with 0.1 μg of mouse monoclonal IgG1; and lane 4, 24-hour worm culture supernatant.

Figure 4.

Anti–Schistosoma japonicum helminth defense molecule 1 (SjHDM-1) immunoglobulin (Ig) G is associated with increased levels of C-reactive protein (CRP) and lower levels of albumin. Serum CRP (A) and albumin (B) levels were analyzed by tertile of the distribution of anti–SjHDM-1 IgG antibody levels in cohort I at baseline, after adjustment for age and S. japonicum infection intensity for both CRP and albumin, as well as hookworm infection intensity for CRP. Bars represent least square means; error bars, standard errors of the mean.

Figure 5.

Anti–Schistosoma japonicum helminth defense molecule 1 (SjHDM-1) immunoglobulin (Ig) G is associated with enlarged liver and spleen sizes. Liver (A) and (B) spleen (B) sizes were analyzed by tertile of the distribution of anti–SjHDM-1 IgG antibody levels in cohort I at baseline, after adjustment for age, Schistosoma japonicum infection intensity, sex, and height for both liver and spleen size as well, as hookworm infection intensity for spleen size. Bars represent least square means; error bars, standard errors of the mean.

Figure 6.

Anti–Schistosoma japonicum helminth defense molecule 1 (SjHDM-1) immunoglobulin (Ig) G is associated with decreased anthropometric measures of chronic nutritional insults. Height, weight, and mid-upper arm circumference (MUAC) were measured and used to calculate body mass index z (BMIZ) (A), MUAC-for-height z (MUACHZ) (B), weight-for-age z (WAZ) (C), and height-for-age z (HAZ) (D) scores for each participant in cohort I; these scores were analyzed by tertile of the distribution of anti–SjHDM-1 IgG antibody levels in cohort I at baseline, after adjustment for age, S. japonicum infection intensity, sex, and socioeconomic status. Bars represent least square means; error bars, standard errors of the mean.