Unraveling cross-reactivity of anti-glycan IgG responses in filarial nematode infections.

Parasitic nematodes responsible for filarial diseases cause chronic disablement in humans worldwide. Elimination programs have substantially reduced the rate of infection in certain areas, but limitations of current diagnostics for population surveillance have been pointed out and improved assays are needed to reach the elimination targets. While serological tests detecting antibodies to parasite antigens are convenient tools, those currently available are compromised by the occurrence of antibodies cross-reactive between nematodes, as well as by the presence of residual antibodies in sera years after treatment and clearance of the infection. We recently characterized the N-linked and glycosphingolipid derived glycans of the parasitic nematode Brugia malayi and revealed the presence of various antigenic structures that triggered immunoglobulin G (IgG) responses in infected individuals. To address the specificity of IgG binding to these glycan antigens, we screened microarrays containing Brugia malayi glycans with plasma from uninfected individuals and from individuals infected with Loa loa, Onchocerca volvulus, Mansonella perstans and Wuchereria bancrofti, four closely related filarial nematodes. IgG to a restricted subset of cross-reactive glycans was observed in infection plasmas from all four species. In plasma from Onchocerca volvulus and Mansonella perstans infected individuals, IgG binding to many more glycans was additionally detected, resulting in total IgG responses similar to the ones of Brugia malayi infected individuals. For these infection groups, Brugia malayi, Onchocerca volvulus and Mansonella perstans, we further studied the different IgG subclasses to Brugia malayi glycans. In all three infections, IgG1 and IgG2 appeared to be the major subclasses involved in response to glycan antigens. Interestingly, in Brugia malayi infected individuals, we observed a marked reduction in particular in IgG2 to parasite glycans post-treatment with anthelminthic, suggesting a promising potential for diagnostic applications. Thus, we compared the IgG response to a broad repertoire of Brugia malayi glycans in individuals infected with various filarial nematodes. We identified broadly cross-reactive and more specific glycan targets, extending the currently scarce knowledge of filarial nematode glycosylation and host anti-glycan antibody response. We believe that our initial findings could be further exploited to develop disease-specific diagnostics as part of an integrated approach for filarial disease control.

Urbanization and Unfavorable Changes in Metabolic Profiles: A Prospective Cohort Study of Indonesian Young Adults.

The substantial increase in the prevalence of non-communicable diseases in Indonesia might be driven by rapid socio-economic development through urbanization. Here, we carried out a longitudinal 1-year follow-up study to evaluate the effect of urbanization, an important determinant of health, on metabolic profiles of young Indonesian adults. University freshmen/women in Jakarta, aged 16−25 years, who either had recently migrated from rural areas or originated from urban settings were studied. Anthropometry, dietary intake, and physical activity, as well as fasting blood glucose and insulin, leptin, and adiponectin were measured at baseline and repeated at one year follow-up. At baseline, 106 urban and 83 rural subjects were recruited, of which 81 urban and 66 rural were followed up. At baseline, rural subjects had better adiposity profiles, whole-body insulin resistance, and adipokine levels compared to their urban counterparts. After 1-year, rural subjects experienced an almost twice higher increase in BMI than urban subjects (estimate (95%CI): 1.23 (0.94; 1.52) and 0.69 (0.43; 0.95) for rural and urban subjects, respectively, Pint < 0.01). Fat intake served as the major dietary component, which partially mediates the differences in BMI between urban and rural group at baseline. It also contributed to the changes in BMI over time for both groups, although it does not explain the enhanced gain of BMI in rural subjects. A significantly higher increase of leptin/adiponectin ratio was also seen in rural subjects after 1-year of living in an urban area. In conclusion, urbanization was associated with less favorable changes in adiposity and adipokine profiles in a population of young Indonesian adults.

Differences in Bacterial Colonization and Mucosal Responses Between High and Low SES Children in Indonesia.

BACKGROUND: Increased nasopharyngeal carriage of pathogenic bacteria is found in low socioeconomic status (SES) settings. How SES affects local immune responses, important for controlling colonization, is currently unknown. OBJECTIVE: Examining bacterial colonization and cytokine response in the nasal mucosa of children from high and low SES. METHODS: Nasosorption samples were collected in October 2019 from 48 high SES and 50 low SES schoolchildren, in a cross-sectional study in Makassar, Indonesia. Twenty-five cytokines were measured in nasal fluid. Quantitative polymerase chain reaction was performed to determine carriage and density of Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and Staphylococcus aureus. Data were analyzed using multivariate regression. RESULTS: H. influenzae and S. pneumoniae densities were increased in low SES settings compared to the high SES settings (P = 0.006, P = 0.026), with 6 and 67 times higher median densities, respectively. Densities of H. influenzae and S. pneumoniae were positively associated with levels of IL-1beta and IL-6. After correcting for bacterial density, IL-6 levels were higher in colonized children from high SES than low SES for H. influenzae and S. pneumoniae (both P = 0.039). CONCLUSION: Increased densities of H. influenzae and S. pneumoniae were observed in low SES children, whereas IL-6 levels associated with colonization were reduced in these children, indicating that immune responses to bacterial colonization were altered by SES.

Intestinal permeability before and after albendazole treatment in low and high socioeconomic status schoolchildren in Makassar, Indonesia.

Intestinal helminths are highly prevalent in low-SES children and could contribute to poor health outcomes either directly or via alteration of the gut microbiome and gut barrier function. We analysed parasitic infections and gut microbiota composition in 325 children attending high- and low-SES schools in Makassar, Indonesia before and after albendazole treatment. Lactulose/Mannitol Ratio (LMR, a marker of gut permeability); I-FABP (a surrogate marker of intestinal damage) as well as inflammatory markers (LBP) were measured. Helminth infections were highly prevalent (65.6%) in low-SES children. LMR and I-FABP levels were higher in low-SES children (geomean (95%CI): 4.03 (3.67-4.42) vs. 3.22 (2.91-3.57); p. adj < 0.001; and 1.57 (1.42-1.74) vs. 1.25 (1.13-1.38); p. adj = 0.02, respectively) while LBP levels were lower compared to the high-SES (19.39 (17.09-22.01) vs. 22.74 (20.07-26.12); p.adj = 0.01). Albendazole reduced helminth infections in low-SES and also decreased LMR with 11% reduction but only in helminth-uninfected children (estimated treatment effect: 0.89; p.adj = 0.01). Following treatment, I-FABP decreased in high- (0.91, p.adj < 0.001) but increased (1.12, p.adj = 0.004) in low-SES children. Albendazole did not alter the levels of LBP. Microbiota analysis showed no contribution from specific bacterial-taxa to the changes observed. Intestinal permeability and epithelial damage are higher while peripheral blood inflammatory marker is lower in children of low-SES in Indonesia. Furthermore, treatment decreased LMR in helminth-uninfected only.

Mass Spectrometric and Glycan Microarray-Based Characterization of the Filarial Nematode Brugia malayi Glycome Reveals Anionic and Zwitterionic Glycan Antigens.

Millions of people worldwide are infected with filarial nematodes, responsible for lymphatic filariasis (LF) and other diseases causing chronic disablement. Elimination programs have resulted in a substantial reduction of the rate of infection in certain areas creating a need for improved diagnostic tools to establish robust population surveillance and avoid LF resurgence. Glycans from parasitic helminths are emerging as potential antigens for use in diagnostic assays. However, despite its crucial role in host-parasite interactions, filarial glycosylation is still largely, structurally, and functionally uncharacterized. Therefore, we investigated the glycan repertoire of the filarial nematode Brugia malayi. Glycosphingolipid and N-linked glycans were extracted from several life-stages using enzymatic release and characterized using a combination of MALDI-TOF-MS and glycan sequencing techniques. Next, glycans were purified by HPLC and printed onto microarrays to assess the host anti-glycan antibody response. Comprehensive glycomic analysis of B. malayi revealed the presence of several putative antigenic motifs such as phosphorylcholine and terminal glucuronic acid. Glycan microarray screening showed a recognition of most B. malayi glycans by immunoglobulins from rhesus macaques at different time points after infection, which permitted the characterization of the dynamics of anti-glycan immunoglobulin G and M during the establishment of brugian filariasis. A significant level of IgG binding to the parasite glycans was also detected in infected human plasma, while IgG binding to glycans decreased after anthelmintic treatment. Altogether, our work identifies B. malayi glycan antigens and reveals antibody responses from the host that could be exploited as potential markers for LF.

Activity of the Toll-like receptor ligands in children with high and low socioeconomic backgrounds.

BACKGROUND: Adjuvants are essential in the induction of immunity by vaccines and interact with receptors, including the Toll-like receptors (TLRs). Responsiveness of these receptors differs between and within populations, which impacts vaccine effectiveness. OBJECTIVE: Here we examine how the innate cytokine response towards TLR ligands differs between high and low socioeconomic status (SES) school-aged children from Makassar, Indonesia. METHODS: We stimulated whole blood from children, of which 27 attended a high SES school and 27 children a low SES school, with ligands for TLR-2/1, -2/6, -3, -4, -5, -7, -9 and measured pro- (TNF) and anti-inflammatory (IL-10) cytokines released. RESULTS: In the low SES there is an increased pro-inflammatory response after 24 h stimulation with TLR-2/1 ligand Pam3 and TLR-4 ligand LPS compared to the high SES. Comparison of the response to LPS after 24 h versus 72 h stimulation revealed that the pro-inflammatory response in the low SES after 24 h shifts to an anti-inflammatory response, whereas in the high SES the initial anti-inflammatory response shifts to a strong pro-inflammatory response after 72 h stimulation. CONCLUSION: We observed differences in the TLR-mediated innate immune response between children attending low and high SES schools, which can have important implications for vaccine development.

Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10-11, 2019.

BACKGROUND: Hookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs. METHODS: As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019. RESULTS: Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures. CONCLUSION: The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting.

The associations of leptin and adiponectin with the metabolic syndrome in an Indonesian and a Dutch population.

BACKGROUND AND AIMS: At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population. METHODS AND RESULTS: We performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia-Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6-1.2) in Indonesian men, 1.1 (0.9-1.4) in Indonesian women, 2.2 (1.6-2.8) in Dutch men, and 1.2 (1.0-1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7-1.2), 0.8 (0.7-1.0), 0.6 (0.6-0.8), and 0.4 (0.4-0.5), respectively. CONCLUSIONS: Despite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI.

Bee- and Wasp-Venom Sensitization in Schoolchildren of High- and Low-Socioeconomic Status Living in an Urban Area of Indonesia.

BACKGROUND: There is not much known about venom allergy in tropical regions. Here, we studied the prevalence of specific IgE (sIgE) and skin prick test (SPT) reactivity and reported sting-related symptoms, in high- and low-socioeconomic status (SES) schoolchildren living in urban city of Makassar in Indonesia. METHODS: Children from high- (n = 160) and low- (n = 165) SES schools were recruited. Standardized questionnaires were used to record information on allergic disorders as well as sting-related symptoms. Parasitic infection, SPT reactivity, and sIgE to Apis mellifera (bee-venom) as well as Vespula spp. (wasp-venom) were assessed. RESULTS: SPT reactivity to bee- and wasp-venom was 14.3 and 12.7%, while the prevalence of sIgE was 26.5 and 28.5%, respectively. When SES was considered, prevalence of SPT to bee- and wasp-venom was higher in high-SES than in low-SES schoolchildren (bee: 22.8 vs. 5.7%, p < 0.001; and wasp: 19.6 vs. 5.7%, p < 0.001). Conversely, sIgE to both venoms was lower in high-SES than in low-SES (bee: 19 vs. 34%, p = 0.016; and wasp: 19 vs. 38%, p = 0.003). Furthermore, among SPT positive subjects, considerable proportion had no detectable sIgE to bee- (65.85%) or wasp-venom (66.67%). Altogether the sensitizations were rarely translated into clinical reaction, as only 1 child reported significant local reaction after being stung. No association with parasitic infections was found. CONCLUSIONS AND CLINICAL RELEVANCE: Sensitization against bee- or wasp-venom is quite prevalent among schoolchildren in Indonesia. The discordance between SPT and sIgE might suggest the direct (non-IgE) effect of venoms in skin reactivity. Recorded sensitizations had poor clinical relevance as they rarely translated into clinical symptoms.

The relationship between malnutrition and TH 2 immune markers: a study in school-aged children of different socio-economic backgrounds in Makassar, Indonesia.

OBJECTIVE: The burden of underweight remains a major problem in Indonesia, and at the same time, the prevalence of overweight is increasing. Malnutrition is a major determinant of health and has been linked to allergic disorders in children. We examined the relationship between malnutrition and TH 2 immune markers in school-aged children in Makassar, Indonesia. METHODS: A cross-sectional study was performed in five schools where socio-demographic characteristics were recorded. Children's standardised z-scores of body mass index (z-BMI) and age-standardised z-scores of height (z-HA) were assessed using WHO child growth standards. Skin prick test (SPT) reactivity was determined to house dust mite allergens. Helminth infection status, (growth) hormones including insulin-like growth factor (IGF-1) and TH 2 immune markers were measured. RESULTS: In total, 954 children were included of whom 21.6% were underweight and 14.8% overweight. After controlling for confounders, overweight was positively associated with leptin (GMR 3.55, 95% CI: 2.99-4.23) and IGF-1 (GMR 1.45, 95% CI: 1.15-1.82), whereas underweight was negatively associated (respectively GMR 0.57, 95% CI: 0.49-0.66 and GMR 0.78, 95% CI: 0.63-0.97). Underweight was associated with a lower eosinophil count (GMR 0.79, 95% CI: 0.64-0.97) but not with total IgE levels or SPT reactivity. Overweight was positively associated with SPT reactivity (adjusted OR 2.68, 95% CI: 1.50-4.78) but no relationship was found with the other TH 2 immune markers. CONCLUSION: Malnutrition is prominent in school-aged children in Makassar, with overweight associated with increased SPT reactivity. Therefore, interventions should focus on undernutrition, but also on overweight to prevent the increase of allergic disorders in Indonesia.

OBJECTIF: La charge de l'insuffisance pondérale reste un problème majeur en Indonésie et parallèlement, la prévalence du surpoids augmente. La malnutrition est un déterminant majeur de la santé et a été associée à des troubles allergiques chez les enfants. Nous avons examiné la relation entre la malnutrition et les marqueurs immunitaires TH 2 chez les enfants d'âge scolaire à Makassar, en Indonésie. MÉTHODES: Etude transversale dans cinq écoles où les caractéristiques sociodémographiques ont été enregistrées. Les scores z standardisés de l'indice de masse corporelle (z-IMC) et les scores z standardisés pour l'âge de la taille (z-HA) pour les enfants ont été évalués en utilisant les normes de croissance de l'enfant de l'OMS. La réactivité du test cutané (SPT) a été déterminée pour les allergènes d'acariens. L'état de l'infection par les helminthes, les hormones (de croissance), y compris le facteur de croissance analogue à l'insuline (IGF-1) et les marqueurs immunitaires TH 2 ont été mesurés. RÉSULTATS: Au total, 954 enfants ont été inclus, dont 21,6% en insuffisance pondérale et 14,8% en surpoids. Après contrôle des facteurs de confusion, le surpoids était positivement associé à la leptine (GMR 3,55, IC95%: 2,99-4,23) et à l'IGF-1 (GMR 1,45 ; IC95%: 1,15-1,82), tandis que l'insuffisance pondérale était associée négativement (respectivement GMR 0,57 ; IC95%: 0,49-0,66 et GMR 0,78 ; IC95%: 0,63-0,97). L'insuffisance pondérale était associée à un nombre plus faible d'éosinophiles (GMR 0,79 ; IC95%: 0,64-0,97) mais pas aux taux d'IgE totaux ou à la réactivité du SPT. Le surpoids était positivement associé à la réactivité du SPT (OR ajusté 2,68 ; IC95%: 1,50-4,78) mais aucune relation n'a été trouvée avec les autres marqueurs immunitaires T H 2. CONCLUSION: La malnutrition est importante chez les enfants d'âge scolaire à Makassar, avec un surpoids associé à une réactivité accrue du SPT. Par conséquent, les interventions devraient se concentrer sur la dénutrition, mais aussi sur le surpoids pour prévenir l'augmentation des troubles allergiques en Indonésie.

Effect of anthelmintic treatment on serum free IGF-1 and IGFBP-3: a cluster-randomized-controlled trial in Indonesia.

In children, soil-transmitted helminth infections have been linked to poor nutritional status and growth retardation in association with lower levels of IGF-1. In adults, IGF-1 has an anabolic and metabolic function and is related to nutritional status. Here, we assessed the impact of helminth infection on free IGF-1 and its major binding protein, IGFBP-3, in adults. The levels of IGF-1 and IGFBP3 were measured in 1669 subjects aged ≥ 16 years, before and after receiving four rounds of albendazole 400 mg/day or matching placebo for three consecutive days. Helminth infection status was assessed by microscopy (Kato-Katz) and PCR. Serum free IGF-1 level was significantly lower in helminth-infected subjects [mean difference and 95% CI - 0.068 (- 0.103; - 0.033), P < 0.001 after adjustment for age, sex, body mass index, and fasting insulin level]. There was no difference in IGFBP-3 level between helminth infected versus non-infected subjects. In the whole study population, albendazole treatment significantly increased serum free IGF-1 level [estimate and 95% CI 0.031 (0.004; - 0.057), P = 0.024] whereas no effect was found on the IGFBP-3 level. Our study showed that helminth infection in adults is associated with lower free IGF-1 levels but not with IGFBP-3 and albendazole treatment significantly increases free IGF-1 levels in the study population.Clinical Trial Registration: https://www.isrctn.com/ISRCTN75636394 .

The Bacterial Gut Microbiota of Schoolchildren from High and Low Socioeconomic Status: A Study in an Urban Area of Makassar, Indonesia.

To understand the relationship between the gut microbiota and the health profile of Indonesians, it is important to elucidate the characteristics of the bacterial communities that prevail in this population. To this end, we profiled the faecal bacterial community of 140 Indonesian schoolchildren in urban Makassar. The core microbiota of Indonesian schoolchildren consisted of Bifidobacterium, Collinsella, and multiple members of the Lachnospiraceae and Ruminicoccaceae families, but the relative abundance of these taxa varied greatly among children. Socioeconomic status (SES) was the main driver for differences in microbiota composition. Multiple bacterial genera were differentially abundant between high and low SES children, including Bifidobacterium, Lactobacillus, Prevotella, and Escherichia-Shigella. In addition, the microbiota of high SES children was less diverse and strongly associated with body mass index (BMI). In low SES children, helminth infection was prevalent and positively associated with Olsenella, Enterohabdus, Lactobacillus, and Mogibacterium abundance, while negatively associated with relative abundance of Prevotella. Protozoa infection was also prevalent, and positively associated with Rikenellaceae, while it was negatively associated with the relative abundance of Romboutsia and Prevotella. In conclusion, Indonesian schoolchildren living in urban Makassar share a core microbiota, but their microbiota varies in diversity and relative abundance of specific bacterial taxa depending on socioeconomic status, nutritional status, and intestinal parasites infection.

A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics.

Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas1. Novel medicines and vaccines are urgently needed2,3. An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4+ T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.

Author Correction: Placental gene expression and antibody levels of mother-neonate pairs reveal an enhanced risk for inflammation in a helminth endemic country.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The prevalence of metabolic syndrome and its association with body fat distribution in middle-aged individuals from Indonesia and the Netherlands: a cross-sectional analysis of two population-based studies.

BACKGROUND: The prevalence of metabolic syndrome varies among populations with different ethnicities. Asian populations develop metabolic complications at lower amounts of adiposity than western populations. The role of abdominal obesity in the metabolic differences between the two populations is poorly understood. OBJECTIVES: Our objectives were to estimate the prevalence of metabolic syndrome and the relative contribution of its components in the Indonesian and the Dutch population, as well as to examine the associations of overall and abdominal obesity with metabolic syndrome. METHODS: In this cross-sectional study of middle-aged adults in the Netherlands Epidemiology of Obesity Study (n = 6602) and the Indonesian National Health Surveillance (n = 10,575), metabolic syndrome was defined by the unified IDF and AHA/NHLBI criteria. We performed logistic and linear regressions to examine associations of BMI and waist circumference with the metabolic syndrome, mutually adjusted for waist circumference and BMI. RESULTS: The prevalence of metabolic syndrome was 28% and 46% in Indonesian men and women, and 36% and 24% in Dutch men and women. The most prominent components were hypertension (61%) and hyperglycemia (51%) in the Indonesian, and hypertension (62%) and abdominal obesity (40%) in the Dutch population. Per SD in BMI and waist circumference, odds ratios (ORs, 95% CI) of metabolic syndrome were 1.5 (1.3-1.8) and 2.3 (1.9-2.7) in Indonesian men and 1.7 (1.2-2.5) and 2.9 (2.1-4.1) in Dutch men. The ORs of metabolic syndrome were 1.4 (1.2-1.6) and 2.3 (2.0-2.7) in Indonesian women and 1.0 (0.8-1.3) and 4.2 (3.2-5.4) in Dutch women. CONCLUSION: More Indonesian women than men have metabolic syndrome, whereas the opposite is true for the Dutch population. In both the Indonesian and the Dutch populations, hypertension is the primary contributor to the prevalence of metabolic syndrome. In both populations, abdominal adiposity was more strongly associated with metabolic syndrome than overall adiposity.

Helminth infections drive heterogeneity in human type 2 and regulatory cells.

Helminth infections induce strong type 2 and regulatory responses, but the degree of heterogeneity of such cells is not well characterized. Using mass cytometry, we profiled these cells in Europeans and Indonesians not exposed to helminths and in Indonesians residing in rural areas infected with soil-transmitted helminths. To assign immune alteration to helminth infection, the profiling was performed before and 1 year after deworming. Very distinct signatures were found in Europeans and Indonesians, showing expanded frequencies of T helper 2 cells, particularly CD161+ cells and ILC2s in helminth-infected Indonesians, which was confirmed functionally through analysis of cytokine-producing cells. Besides ILC2s and CD4+ T cells, CD8+ T cells and γδ T cells in Indonesians produced type 2 cytokines. Regulatory T cells were also expanded in Indonesians, but only those expressing CTLA-4, and some coexpressed CD38, HLA-DR, ICOS, or CD161. CD11c+ B cells were found to be the main IL-10 producers among B cells in Indonesians, a subset that was almost absent in Europeans. A number of the distinct immune profiles were driven by helminths as the profiles reverted after clearance of helminth infections. Moreover, Indonesians with no helminth infections residing in an urban area showed immune profiles that resembled Europeans rather than rural Indonesians, which excludes a major role for ethnicity. Detailed insight into the human type 2 and regulatory networks could provide opportunities to target these cells for more precise interventions.

Placental gene expression and antibody levels of mother-neonate pairs reveal an enhanced risk for inflammation in a helminth endemic country.

In utero exposure to environmental factors can modify the development of allergies later in life whereby the mechanisms of the feto-maternal crosstalk still remain largely unknown. Murine studies revealed that inflammatory maternal signals elicited by chronic helminth infection within the placenta imprint a distinct gene expression profile related to the Vitamin-D-receptor (VDR)-inflammation-axis. We thus investigated whether pro- or anti- inflammatory immune responses as well as VDR and related gene expression within the placenta differ between women from helminth-endemic and non-endemic areas. A prospective pilot study was conducted in Munich, Germany (helminth non-endemic) and Lambaréné, Gabon (helminth-endemic). At delivery, clinical information alongside placenta tissue samples and maternal and cord blood were obtained for further laboratory analysis. Schistosoma haematobium infection was detected in 13/54 (23%) Gabonese women. RT PCR revealed significantly lower gene expression of VDR, Cyp27b1, Foxp3 and IL10 in Gabonese compared to German placentae as well as significantly lower levels of plasma IgG4 in newborns resulting in a significantly higher IgE/IgG4 ratio. These findings demonstrate that exposure in utero to different environments alters placental gene expression and thus possibly plays a role in the development and modulation of the immune system of the offspring.

The Effect of Gut Microbiome Composition on Human Immune Responses: An Exploration of Interference by Helminth Infections.

Background: Soil-transmitted helminths have been shown to have the immune regulatory capacity, which they use to enhance their long term survival within their host. As these parasites reside in the gastrointestinal tract, they might modulate the immune system through altering the gut bacterial composition. Although the relationships between helminth infections or the microbiome with the immune system have been studied separately, their combined interactions are largely unknown. In this study we aim to analyze the relationship between bacterial communities with cytokine response in the presence or absence of helminth infections. Results: For 66 subjects from a randomized placebo-controlled trial, stool and blood samples were available at both baseline and 21 months after starting three-monthly albendazole treatment. The stool samples were used to identify the helminth infection status and fecal microbiota composition, while whole blood samples were cultured to obtain cytokine responses to innate and adaptive stimuli. When subjects were free of helminth infection (helminth-negative), increasing proportions of Bacteroidetes was associated with lower levels of IL-10 response to LPS {estimate [95% confidence interval (CI)] -1.96 (-3.05, -0.87)}. This association was significantly diminished when subjects were helminth-infected (helminth positive) (p-value for the difference between helminth-negative versus helminth-positive was 0.002). Higher diversity was associated with greater IFN-γ responses to PHA in helminth-negative (0.95 (0.15, 1.75); versus helminth-positive [-0.07 (-0.88, 0.73), p-value = 0.056] subjects. Albendazole treatment showed no direct effect in the association between bacterial proportion and cytokine responses, although the Bacteroidetes' effect on IL-10 responses to LPS tended downward in the albendazole-treated group [-1.74 (-4.08, 0.59)] versus placebo [-0.11 (-0.84, 0.62); p-value = 0.193]. Conclusion: We observed differences in the relationship between gut microbiome composition and immune responses, when comparing individuals infected or uninfected with geohelminths. Although these findings are part of a preliminary exploration, the data support the hypothesis that intestinal helminths may modulate immune responses, in unison with the gut microbiota. Trial Registration: ISRCTN, ISRCTN83830814. Registered 27 February 2008 - Retrospectively registered, http://www.isrctn.com/ISRCTN83830814.

BCG scar, socioeconomic and nutritional status: a study of newborns in urban area of Makassar, Indonesia.

OBJECTIVE: To investigate factors that determine the response to Bacille Calmette-Guérin (BCG) vaccination in urban environments with respect to socioeconomic status (SES), prenatal exposure to infections or newborn's nutritional status. METHODS: The study was conducted in an urban area, in Makassar, Indonesia. At baseline, 100 mother and newborns pair from high and low SES communities were included. Intestinal protozoa, soil transmitted helminths, total IgE, anti-Hepatitis A Virus IgG and anti-Toxoplasma IgG were measured to determine exposure to infections. Information on gestational age, birth weight/height and delivery status were collected. Weight-for-length z-score, a proxy for newborns adiposity, was calculated. Leptin and adiponectin from cord sera were also measured. At 10 months of age, BCG scar size was measured from 59 infants. Statistical modelling was performed using multiple linear regression. RESULTS: Both SES and birth nutritional status shape the response towards BCG vaccination at 10 months of age. Infants born to low SES families have smaller BCG scar size compared to infants born from high SES families and total IgE contributed to the reduced scar size. On the other hand, infants born with better nutritional status were found to have bigger BCG scar size but this association was abolished by leptin levels at birth. CONCLUSION: This study provides new insights into the importance of SES and leptin levels at birth on the development of BCG scar in 10 months old infants.

OBJECTIF: Investiguer les facteurs qui déterminent la réponse à la vaccination par le BCG en milieu urbain en ce qui concerne le statut socioéconomique (SSE), l'exposition prénatale aux infections ou l'état nutritionnel du nouveau-né. MÉTHODES: L'étude a été menée dans une zone urbaine, à Makassar, en Indonésie. Au départ, 100 paires mère-nouveau-né issues de communautés à statut social élevé et faible ont été incluses. Les protozoaires intestinaux, les helminthes transmis par le sol, les IgE totales, les IgG anti-virus de l'hépatite A et anti- Toxoplasma ont été mesurés pour déterminer l'exposition aux infections. Des informations sur l'âge gestationnel, le poids/taille à la naissance et l'état d'accouchement ont été collectées. Le z-score poids-pour la taille, un indicateur indirect de l'adiposité du nouveau-né a été calculé. La leptine et l'adiponectine provenant de sérum des cordons ont également été mesurées. A l'âge de 10 mois, la taille des cicatrices de BCG a été mesurée chez 59 nourrissons. La modélisation statistique a été réalisée à l'aide d'une régression linéaire multiple. RÉSULTATS: Le statut socioéconomique et l'état nutritionnel à la naissance déterminent la réponse à la vaccination par le BCG à l'âge de 10 mois. La taille des cicatrices de BCG est plus petite chez les nourrissons nés de familles à statut socioéconomique faible comparée à celles chez ceux de familles à statut socioéconomique élevé et les IgE totales ont contribué à la réduction de la taille de ces cicatrices. En revanche, les bébés nés avec un meilleur état nutritionnel avaient une taille de cicatrice du BCG plus grande, mais cette association était supprimée par les niveaux de leptine à la naissance. CONCLUSION: Cette étude fournit de nouvelles informations sur l'importance du SSE et des niveaux de leptine à la naissance sur le développement d'une cicatrice du BCG chez des nourrissons âgés de 10 mois.

Deworming children for soil-transmitted helminths in low and middle-income countries: systematic review and individual participant data network meta-analysis.

Intestinal parasites affect millions of children globally. We aimed to assess effects of deworming children on nutritional and cognitive outcomes across potential effect modifiers using individual participant data (IPD). We searched multiple databases to 27 March 2018, grey literature, and other sources. We included randomised and quasi randomised trials of deworming compared to placebo or other nutritional interventions with data on baseline infection. We used a random-effects network meta-analysis with IPD and assessed overall quality, following a pre-specified protocol. We received IPD from 19 trials of STH deworming. Overall risk of bias was low. There were no statistically significant subgroup effects across age, sex, nutritional status or infection intensity for each type of STH. These analyses showed that children with moderate or heavy intensity infections, deworming for STH may increase weight gain (very low certainty). The added value of this review is an exploration of effects on growth and cognition in children with moderate to heavy infections as well as replicating prior systematic review results of small effects at the population level. Policy implications are that complementary public health strategies need to be assessed and considered to achieve growth and cognition benefits for children in helminth endemic areas.