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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., (© 2022. The Author(s).)

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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminth-specific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo-estimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (P time ) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4 + T cells of albendazole-treated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; P time = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries., Competing Interests: The authors declare no conflict of interest.

Deworming is rightly advocated to prevent helminth-induced morbidity. Nevertheless, in affluent countries, the deliberate infection of patients with worms is being explored as a possible treatment for inflammatory diseases. Several clinical trials are currently registered, for example, to assess the safety or efficacy of Trichuris suis ova in allergies, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, and autism, and the Necator americanus larvae for allergic rhinitis, asthma, coeliac disease, and multiple sclerosis. Studies in animals provide strong evidence that helminths can not only downregulate parasite-specific immune responses, but also modulate autoimmune and allergic inflammatory responses and improve metabolic homoeostasis. This finding suggests that deworming could lead to the emergence of inflammatory and metabolic conditions in countries that are not prepared for these new epidemics. Further studies in endemic countries are needed to assess this risk and to enhance understanding of how helminths modulate inflammatory and metabolic pathways. Studies are similarly needed in non-endemic countries to move helminth-related interventions that show promise in animals, and in phase 1 and 2 studies in human beings, into the therapeutic development pipeline., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Helminth infections are highly prevalent in developing countries, especially in rural areas. With gradual development, there is a transition from living conditions that are dominated by infection, poor sanitation, manual labor, and traditional diet to a situation where burden of infections is reduced, infrastructure is improved, sedentary lifestyle dominates, and processed food forms a large proportion of the calorie intake. The combinations of some of the changes in lifestyle and environment are expected to result in alteration of the landscape of diseases, which will become dominated by non-communicable disorders. Here we review how the major helminth infections affect a large proportion of the population in the developing world and discuss their impact on the immune system and the consequences of this for other infections which are co-endemic in the same areas. Furthermore, we address the issue of decreasing helminth infections in many parts of the world within the context of increasing inflammatory, metabolic, and cardiovascular diseases.

Chronic helminth infections are often associated with a reduced prevalence of inflammatory disorders, including allergic diseases. Helminths influence the host immune system by downregulating T-cell responses; the cytokine IL-10 appears to play a central role in this process. Over the last decade, evidence has emerged toward a new regulatory cell type: IL-10-producing B cells, capable of regulating immunity and therefore termed regulatory B cells. Initially, regulatory B cells have been described in autoimmunity models where they dampen inflammation, but recently they were also found in several helminth infection models. Importantly, regulatory B cells have recently been identified in humans, and it has been suggested that patients suffering from autoimmunity have an impaired regulatory B-cell function. As such, it is of therapeutic interest to study the conditions in which IL-10-producing B cells can be induced. Chronic helminth infections appear to hold promise in this context as emerging evidence suggests that helminth-induced regulatory B cells strongly suppress allergic inflammation. In this review, we will discuss the conditions under which regulatory B cells are present, leading to a state of tolerance, as well as the conditions where their absence or functional impairment leads to exacerbated disease. We will summarize their phenotypic characteristics and their mechanisms of action and elaborate on possible mechanisms whereby regulatory B cells can be induced or expanded, as this may open novel avenues for the treatment of inflammatory diseases, such as allergic asthma., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Developed countries are suffering from an epidemic rise in immunologic disorders, such as allergy-related diseases and certain autoimmunities. Several studies have demonstrated a negative association between helminth infections and inflammatory diseases (eg, allergy), providing a strong case for the involvement of helminth infections in this respect. However, some studies point in the opposite direction. The discrepancy may be explained by differences in frequency, dose, time, and type of helminth. In this review, new studies are discussed that may support the concept that chronic helminth infections in particular-but not acute infections-are associated with the expression of regulatory networks necessary for downmodulating allergic immune responses to harmless antigens. Furthermore, different components of regulatory networks are highlighted, such as the role of regulatory T and B cells, modulation of dendritic cells, early innate signals from structural cells (eg, epithelial cells), and their individual contributions to protection against allergic diseases. It is of great interest to define and characterize specific helminth molecules that have profound immunomodulatory capacities as targets for therapeutic application in the treatment or prophylaxis of allergic manifestations.

Worldwide, more than a billion people are infected with helminths. These worm infections generally do not lead to mortality, however, they are chronic in nature and can lead to considerable morbidity. Immunologically these infections are interesting; chronic helminth infections are characterized by skewing towards a T helper 2 type response as well as regulatory responses. The regulatory network is associated with chronic helminth infections and is thought to prevent strong immune responses against parasitic worms, allowing their long-term survival and restricting pathology. This regulatory network is thought to also temper responses to non-helminth antigens, like allergens or self-antigens, possibly leading to lower prevalence of allergies and autoimmune diseases in subjects that are chronically infected with helminths. This raises the interesting idea that helminths may bear molecules that have potential therapeutic action against allergies and possibly other inflammatory diseases. However, on the other side of the coin, this would predict that helminth infected subjects might not respond strongly to third party antigens like vaccines. This is an important issue, since most vaccines that are being developed against diseases such as HIV, tuberculosis or malaria will be introduced in areas where helminth infections are highly prevalent. Moreover, these vaccines are proving difficult to develop and are often weak, thus any confounder that would affect their efficacy needs to be taken into consideration. Helminth derived molecules have been identified that induce T helper 2 and regulatory responses via modulation of dendritic cells and some appear to do so via Toll like receptor (TLR) signaling. New insights into these pathways could be useful to antagonize suppression and hence boost vaccine efficacy or to optimize suppression induced by helminth derived molecules and control inflammatory diseases.

Immunology was founded by studying the body's response to infectious microorganisms, and yet microbial prokaryotes only tell half the story of the immune system. Eukaryotic pathogens--protozoa, helminths, fungi and ectoparasites--have all been powerful selective forces for immune evolution. Often, as with lethal protozoal parasites, the focus has been on acute infections and the inflammatory responses they evoke. Long-lived parasites such as the helminths, however, are more remarkable for their ability to downregulate host immunity, protecting themselves from elimination and minimizing severe pathology in the host.

Objective: To report the prevalence of polyparasitism during pregnancy in the Lambaréné region of Gabon and its association with newborn birth weight. Method: Pregnant women in their third trimester were recruited in a prospective study between November 2011 and March 2015. Parasite infection status was assessed microscopically in stool, urine and blood samples. Maternal demographic and obstetrical characteristics and newborns anthropometric data were collected. Multivariable logistic regression was used to assess the association between low birth weight and polyparasitism. Results: 678 of 927 pregnant women were included for analysis with mean age (SD) of 25 (6.8) years. The analysis showed that 69% (468/678) were infected with at least one parasite (Plasmodium spp., Schistosoma spp., soil‐transmitted helminths, filarial infections). This comprised of 38% with monoparasitism and 31% polyparasitism. The proportion of newborn babies with a weight below 2500 g (LBW) in our study was 21% (142/678). Compared to pregnant women without infection, women with monoparasitic infection had adjusted Odds Ratio confidence interval 95% CI (aOR [95%CI]) of 1.6 [0.95–2.73], those with two parasites had aOR 95%CI of 2.63 [1.51–4.62], and those with more than two parasites had aOR of 5.08 [2.5–10.38] for delivering a newborn with low birth weight. Conclusion: In Lambaréné, an endemic area for multiple parasite infections, there is a high prevalence of polyparasitism in pregnant women. Polyparasitism is associated with low birth weight. Therefore, there is an urgent need for active screening and treatment of parasite infections in pregnant women to assess the potential public health benefit of such interventions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Parasitic helminths evade, skew and dampen human immune responses through numerous mechanisms. Such effects will likely have consequences for HIV-1 transmission and disease progression. Here we analyzed the effects that soluble egg antigen (SEA) from Schistosoma mansoni had on modulating HIV-1 infection and cytokine/chemokine production in vitro. We determined that SEA, specifically through kappa-5, can potently bind to DC-SIGN and thereby blocks DC-SIGN mediated HIV-1 trans-infection (p<0.05) whilst not interfering with cis-infection. DCs exposed to SEA whilst maturing under Th2 promoting conditions, will upon co-culture with naïve T-cells induce a T-cell population that was less susceptible to HIV-1 R5 infection (p<0.05) compared to DCs unexposed to SEA, whereas HIV-1 X4 virus infection was unaffected. This was not observed for DCs exposed to SEA while maturing under Th1 or Th1/Th2 (Tmix) promoting conditions. All T-cell populations induced by SEA exposed DCs demonstrate a reduced capacity to produce IFN-γ and MIP-1β. The infection profile of T-cells infected with HIV-1 R5 was not associated with down-modulation of CCR5 cell surface expression. We further show that DCs maturing under Tmix conditions exposed to plant recombinant omega-1 protein (rω-1), which demonstrates similar functions to natural ω-1, induced T-cell populations that were less sensitive for HIV-1 R5 infection (p<0.05), but not for X4 virus infection. This inhibition associated again with a reduction in IFN-γ and MIP-1β expression, but additionally correlated with reduced CCR5 expression. We have shown that SEA parasite antigens and more specifically rω-1 can modulate HIV-1 infectivity with the potential to influence disease course in co-infected individuals. [ABSTRACT FROM AUTHOR]

Summary: Background: It is proposed that helminth exposure protects against allergy‐related disease, by mechanisms that include disconnecting risk factors (such as atopy) from effector responses. Objective: We aimed to assess how helminth exposure influences rural‐urban differences in risk factors for allergy‐related outcomes in tropical low‐ and middle‐income countries. Methods: In cross‐sectional surveys in Ugandan rural Schistosoma mansoni (Sm)‐endemic islands, and in nearby mainland urban communities with lower helminth exposure, we assessed risk factors for atopy (allergen‐specific skin prick test [SPT] reactivity and IgE [asIgE] sensitization) and clinical allergy‐related outcomes (wheeze, urticaria, rhinitis and visible flexural dermatitis), and effect modification by Sm exposure. Results: Dermatitis and SPT reactivity were more prevalent among urban participants, urticaria and asIgE sensitization among rural participants. Pairwise associations between clinical outcomes, and between atopy and clinical outcomes, were stronger in the urban survey. In the rural survey, SPT positivity was inversely associated with bathing in lakewater, Schistosoma‐specific IgG4 and Sm infection. In the urban survey, SPT positivity was positively associated with age, non‐Ugandan maternal tribe, being born in a city/town, BCG scar and light Sm infection. Setting (rural vs urban) was an effect modifier for risk factors including Sm‐ and Schistosoma‐specific IgG4. In both surveys, the dominant risk factors for asIgE sensitization were Schistosoma‐specific antibody levels and helminth infections. Handwashing and recent malaria treatment reduced odds of asIgE sensitization among rural but not urban participants. Risk factors for clinical outcomes also differed by setting. Despite suggestive trends, we did not find sufficient evidence to conclude that helminth (Sm) exposure explained rural‐urban differences in risk factors. Conclusions and clinical relevance: Risk factors for allergy‐related outcomes differ between rural and urban communities in Uganda but helminth exposure is unlikely to be the sole mechanism of the observed effect modification between the two settings. Other environmental exposures may contribute significantly. [ABSTRACT FROM AUTHOR]

Background: Eosinophils are a prominent cell type in the host response to helminths, and some evidence suggests that neutrophils might also play a role. However, little is known about the activation status of these granulocytes during helminth infection.Methods: We analyzed the expression of eosinophil and neutrophil activation markers in peripheral blood by flow cytometry and measured serum levels of eosinophil granule proteins in 300 subjects residing in an area endemic for soil-transmitted helminths (STH). The data generated are on samples before and after 1 year of 3-monthly albendazole treatment.Results: Anthelmintic treatment significantly reduced the prevalence of STH. While eosinophil numbers were significantly higher in STH-infected compared to uninfected subjects and significantly decreased following albendazole treatment, there was no effect exerted by the helminths on either eosinophil nor neutrophil activation. Although at baseline eosinophil granule protein levels were not different between STH-infected and uninfected subjects, treatment significantly reduced the levels of eosinophil-derived neurotoxin (EDN) in those infected at baseline.Conclusions: These results show that besides decreasing eosinophil numbers, anthelmintic treatment does not significantly change the activation status of eosinophils, nor of neutrophils, and the only effect seen was a reduction in circulating levels of EDN.Clinical Trials Registration: http://www.isrctn.com/ISRCTN75636394. [ABSTRACT FROM AUTHOR]

Background: In many rural areas of tropical countries such as Indonesia, the prevalence of soil-transmitted helminths (STH) infections remains high. At the same time, the burden of allergic disorders in such rural areas is reported to be low and inversely associated with helminth infections. To reduce the morbidity and transmission of helminth infections, the world health organization recommends preventive treatment of school children by providing mass drug administration (MDA) with albendazole. Here, we had an opportunity to evaluate the prevalence of skin reactivity to allergens before and after albendazole treatment to get an indication of the possible impact of MDA on allergic sensitization. Methods: A study was conducted among 150 school children living in an area endemic for STH infections. Before and 1 year after anthelminthic treatment with albendazole, stool samples were examined for the presence of STH eggs, skin prick tests (SPT) for cockroach and house dust mites were performed, blood eosinophilia was assessed, and total immunoglobulin E (IgE) and C-reactive protein (CRP) were measured in plasma. Results: Anthelminthic treatment significantly reduced the prevalence of STH from 19.6 before treatment to 6% after treatment (p < 0.001). Levels of total IgE (estimate: 0.30; 95% CI 0.22–0.42, p < 0.0001), CRP (estimate: 0.60; 95% CI 0.42–0.86, p = 0.006), and eosinophil counts (estimate: 0.70; 95% CI 0.61–0.80, p < 0.001) decreased significantly. The prevalence of SPT positivity increased from 18.7 to 32.7%. Multivariate analysis adjusted for confounding factors showed an increased risk of being SPT positive to any allergen (OR 3.04; 95% CI 1.338–6.919, p = 0.008). Conclusions: This study indicates that 1 year of MDA with albendazole was associated with a reduced prevalence of STH infections. This study shows that the prevalence of allergic sensitization increases after 1 year of albendazole treatment. Placebo-controlled and larger studies are needed to further substantiate a role of deworming treatment in an increased risk of allergic sensitization. [ABSTRACT FROM AUTHOR]

Background: Microbiome studies suggest the presence of an interaction between the human gut microbiome and soil-transmitted helminth. Upon deworming, a complex interaction between the anthelminthic drug, helminths and microbiome composition might occur. To dissect this, we analyse the changes that take place in the gut bacteria profiles in samples from a double blind placebo controlled trial conducted in an area endemic for soil transmitted helminths in Indonesia. Methods: Either placebo or albendazole were given every three months for a period of one and a half years. Helminth infection was assessed before and at 3 months after the last treatment round. In 150 subjects, the bacteria were profiled using the 454 pyrosequencing. Statistical analysis was performed cross-sectionally at pre-treatment to assess the effect of infection, and at post-treatment to determine the effect of infection and treatment on microbiome composition using the Dirichlet-multinomial regression model. Results: At a phylum level, at pre-treatment, no difference was seen in microbiome composition in terms of relative abundance between helminth-infected and uninfected subjects and at post-treatment, no differences were found in microbiome composition between albendazole and placebo group. However, in subjects who remained infected, there was a significant difference in the microbiome composition of those who had received albendazole and placebo. This difference was largely attributed to alteration of Bacteroidetes. Albendazole was more effective against Ascaris lumbricoides and hookworms but not against Trichuris trichiura, thus in those who remained infected after receiving albendazole, the helminth composition was dominated by T. trichiura. Discussion: We found that overall, albendazole does not affect the microbiome composition. However, there is an interaction between treatment and helminths as in subjects who received albendazole and remained infected there was a significant alteration in Bacteroidetes. This helminth-albendazole interaction needs to be studied further to fully grasp the complexity of the effect of deworming on the microbiome. Trial registration: ISRCTN Registy, . [ABSTRACT FROM AUTHOR]

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently—in an autocrine manner—induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1–independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2−/−, and to a lesser extent Dectin-1−/− mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced. [ABSTRACT FROM AUTHOR]

Ecological theory suggests that co-infecting parasite species can interact within hosts directly, via host immunity and/or via resource competition. In mice, competition for red blood cells (RBCs) between malaria and bloodsucking helminths can regulate malaria population dynamics, but the importance of RBC competition in human hosts was unknown. We analysed infection density (i.e. the concentration of parasites in infected hosts), from a 2-year deworming study of over 4000 human subjects. After accounting for resource-use differences among parasites, we find evidence of resource competition, priority effects and a competitive hierarchy within co-infected individuals. For example reducing competition via deworming increased Plasmodium vivax densities 2.8-fold, and this effect is limited to bloodsucking hookworms. Our ecological, resource-based perspective sheds new light into decades of conflicting outcomes of malaria-helminth co-infection studies with significant health and transmission consequences. Beyond blood, investigating within-human resource competition may bring new insights for improving human health. [ABSTRACT FROM AUTHOR]

Background: Dendritic cells (DCs) are the sentinels of the immune system. Upon recognition of a pathogen, they mature and migrate to draining lymph nodes to prime and polarize T cell responses. Although it is known that helminths and helminth-derived molecules condition DCs to polarize T helper (Th) cells towards Th2, the underlying mechanisms remain incompletely understood. Objectives: The aim of this study was to conduct a proteome analysis of helminth antigen- stimulated DCs in order to gain more insight into the cellular processes associated with their ability to polarize immune responses. Methods: We analyzed the maturation and polarization of monocyte-derived DCs from 9 donors at 2 different time points after stimulation with different Th1- and Th2-polarizing pathogen-derived molecules. The samples were measured using liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry for relative quantitation. Results: Lipopolysaccharide-induced maturation promoted the expression of proteins related to metabolic, cellular, and immune system processes. Th1-polarizing DCs, conditioned by IFN-γ during maturation, displayed accelerated maturation by differentially expressing cytoskeletal proteins and proteins involved in immune regulation. The stimulation of DCs with soluble egg antigens and omega-1 derived from Schistosoma mansoni , which are both Th2-inducing stimuli, increased 60S acidic ribosomal protein P2, and vesicle amine transferase 1 while decreasing the expression of proteins related to antigen processing and presentation. Conclusion: Our data indicate that not only proteins involved in the interaction between T cells and DCs at the level of the immunological synapse, but also those related to cellular metabolism and stress, may promote Th2 polarization. [ABSTRACT FROM AUTHOR]

The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation. [ABSTRACT FROM AUTHOR]

Background: Helminths and malaria are among the most prevalent infectious diseases in the world. They both occur in tropical area where they often affect the same populations. There are studies suggesting an effect of helminths on malariometric indices. For example, malaria attacks as well as disease severity has been shown to be influenced by a concurrent chronic helminth infection. However, there are also studies that show no effect of concurrent helminth infections on malarial outcomes. To start addressing this issue, the effect of chronic Schistosoma haematobium infection on both the innate and adaptive immune response of Plasmodium falciparum-infected subjects was assessed in an area endemic for both these infections in Gabon. Method: Subjects infected with S. haematobium and or P. falciparum, as well as a control group with neither of these infections, were recruited. For innate immune response, heparinized blood was obtained and cultured for 24 hours with a panel of TLR ligands. For adaptive immune response, PBMC was isolated and stimulated with SEB for 72 hours. Cytokines and chemokines were measured in supernatants using a multiplex beads array immunoassay. Principal Component analysis was used to assess pattern of cytokine and chemokine responses representing the innate and adaptive components of the immune system. Results: Overall it was observed that the presence of P. falciparum infection was marked by an increase in innate and adaptive immune responsiveness while S. haematobium infection was characterized by an increased chemokine profile, with at the same time, lower pro inflammatory markers. When the study subjects were split into single infected and co-infected groups no effect of S. haematobium on the immune response of P. falciparum infected subjects was observed, neither for the innate nor for the adaptive component of the immune response. Conclusion: This study provides original information on the cellular immune response of S. haematobium and/or P. falciparum in infected subjects. It rules out an effect of S. haematobium on the cytokine profile of subjects co-infected with P. falciparum. [ABSTRACT FROM AUTHOR]

Nearly one quarter of the world's population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells that mediate anti-helminth immunity. In addition, recent literature describes a close association between type 2 immune responses and wound repair, suggesting that aTh2 response may concurrently mediate repair of parasite-induced damage. The molecular mechanisms that govern Th2 responses are poorly understood, although it is clear that dendritic cells (DCs), which are the most efficient antigen-presenting cells in the immune system, play a central role. Here, we review the molecular mechanisms by which DCs polarizeTh2 cells, examining both helminth antigens and helminth-mediated tissue damage asTh2-inducing triggers. Finally, we discuss the implication of these findings in the context of metabolic disorders, as recent literature indicates that various aspects of the Th2-associated inflammatory response contribute to metabolic homeostasis. [ABSTRACT FROM AUTHOR]

The article discusses the inverse association between helminth infections and inflammatory diseases like allergies and inflammatory bowel disease and a lower incidence of metabolic syndrome (MetS). Topics discussed include a study in India which noted an inverse association between lymphatic filariasis and type 2 diabetes (T2D) and a study in rural Indonesia which showed negative association between intestinal helminth infections in adults with risk factors for cardiovascular disease.

The last few decades have seen a marked increase in the global prevalence of allergic diseases particularly among children. Among the factors attributed to this rise has been reduced exposure to pathogens during childhood leading to insufficient maturation of the regulatory arm of developing immune systems. Over the years, a number of epidemiological studies have observed an inverse relationship between parasitic worm (helminth) infections and allergies. The purpose of this review is to highlight insights from population studies conducted among children published between 2008 and 2013 that explore the complex dynamics between helminth infections and allergies. These insights include the effect of anthelmintic treatment on allergic responses, an elucidation of immune mechanisms and an examination of helminth-induced immunoglobulin E cross-reactivity. A better understanding of the relationship between helminths and allergies is imperative as research directions move toward harnessing the therapeutic potential of helminths and their products in the treatment of allergic disorders. [ABSTRACT FROM AUTHOR]

Background: The association between allergen skin sensitization and helminth infection has been debated for years. Here, we sought to estimate the prevalence of atopic sensitization of residents living in area endemic for lymphatic filariasis and intestinal helminths and to investigate the association between these different species of helminths with allergen skin test reactivity to allergens. Methods: Five hundred and eighty-three individuals living in an area endemic for Brugia malayi and for intestinal helminths were skin prick tested using 3 allergens. Microfilariae were enumerated by filtration of 1 ml nocturnally collected blood, and 442 stool samples were examined for the presence of intestinal helminth eggs. Results: The prevalence of skin prick test positivity to any allergen was 23.5% (to cockroach 20.6%, to house dust mite 6.2% and to grass pollen 1.2%). Individuals with B. malayi infection had a significantly reduced risk for atopic reactivity to cockroach (adjusted odds ratio 0.56, 95% CI 0.35-0.88). In the same population, no association was found between the presence of intestinal helminths and any skin test reactivity. Conclusions: In a general population, across all ages in a rural area of Indonesia, the prevalence of skin test reactivity to house dust mite is as low as in other non-affluent countries, and infection with B. malayi appears to reduce the risk of skin reactivity to cockroach. On the other hand, we found no association between infection with intestinal helminths and skin test reactivity to aeroallergens. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Inflammatory diseases are on the rise in westernized countries, but also in urbanized areas of developing countries. A number of studies have now demonstrated a negative association between helminth infections and inflammatory diseases, such as allergy, suggesting a potential role for helminth-induced immune responses. However, this is not the case for all studies. In this review both supporting and opposing literature on the role of helminth infections, particularly in allergy, are discussed. Furthermore, the concept is put forward that chronic helminth infections, but not acute infections, may be associated with the expression of regulatory networks necessary for downmodulating allergic immune responses to harmless antigens. Lastly, different components of helminth-induced regulatory networks are detailed, such as the role of regulatory T and B cells, modulation of dendritic cells, the presence of suppressory alternatively activated macrophages, and their individual contributions to protection against allergic diseases. Advantage should be taken from this knowledge to identify and select individual helminth-derived molecules that may harbor therapeutic potential against inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Allergy and helminth infections share key immunological features in terms of Th2 responses. Although in industrialized countries clustering of allergic disorders within families has been frequently reported, such information is lacking from areas where helminth infections are endemic. Methods: A total of 466 subjects from 29 families and 112 households participated in this study. Filarial infection, skin test reactivity and IgE to mite as well as total IgE were measured in all samples. Clustering of the allergy-related outcomes due to genetic and household factors was tested. Results: Genetic factors contributed significantly to the clustering of total IgE and allergen-specific IgE, whereas only household factors contributed to the clustering of SPT positivity. Conclusion: Similar to several studies conducted in western populations, total IgE and allergen-specific IgE are influenced by genetic factors in a population resident in a helminth endemic area. However, clustering of SPT positivity due to genetic factors was not significant in the current study raising the question of whether the presence of helminth infections may override genes that are associated with the expression of tissue reactivity to allergens in the west. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Several studies have shown an inverse association between helminth infections and atopy, but none have clearly established that the pathogens themselves, rather than other associated factors, cause the suppression of atopy. To show a direct link, prospective intervention studies are required. Methods. A randomized, controlled trial was performed to study whether repeated anthelminthic treatment results in increased allergic sensitivity to house dust mites (HDMs) in chronically infected children. The trial population consisted of 317 Gabonese schoolchildren with a high prevalence of intestinal helminths. Intervention consisted of treatment every 3 months with praziquantel and mebendazole and with placebo in the control group. Follow-up lasted 30 months: at 6-month intervals, skin-test sensitivity to mites, helminth infection status, and levels of total IgE were determined. Results. Treatment resulted in a significant increase in the rate of developing skin sensitivity to HDMs (hazard ratio, 2.51; 95% confidence interval, 1.85-3.41), which was mediated, in part, by reductions in Ascaris and/or Trichuris infections. Levels of total IgE were reduced, but this did not mediate the effect of treatment on skin-test reactivity. Conclusions. Anthelminthic treatment of chronically infected children results in increased atopic reactivity, which indicates that helminths directly suppress allergic reactions. [ABSTRACT FROM AUTHOR]

Helminths are multicellular pathogens which infect vast numbers of human and animal hosts, causing widspread chronic disease and morbidity. Vaccination against these parasites requires more than identification of effective target antigens, because without understanding the immunology of the host-parasite relationship, ineffective immune mechanisms may be invoked, and there is a danger of amplifying immunopathogenic responses. The fundamental features of the immune response to helminths are therefore summarised in the context of vaccines to helminth parasites. The contention between type-1 and type-2 responses is a central issue in helminth infections, which bias the immune system strongly to the type-2 pathway. Evidence from both human and experimental animal infections indicates that both lineages contribute to immunity in differing circumstances, and that a balanced response leads to the most favorable outcome. A diversity of immune mechanisms can be brought to bear on various helminth species, ranging from antibody-independent macrophages, antibody-dependent granulocyte killing, and non-lymphoid actions, particularly in the gut. This diversity is highlighted by analysis of rodent infections, particularly in comparisons of cytokine-depleted and gene-targeted animals. This knowledge of protective mechanisms needs to be combined with a careful choice of parasite antigens for vaccines. Many existing candidates have been selected with host antibodies, rather than T-cell responses, and include a preponderance of highly conserved proteins with similarities to mammalian or invertebrate antigens. Advantage has yet to be taken of parasite genome projects, or of directed searches for novel, parasite-specific antigens and targets expressed... [ABSTRACT FROM AUTHOR]

IgG4 and IgE isotypes contribute marginally to the pool of circulating antibodies in healthy individuals, but are elevated during atopic diseases and particularly upon helminth infections. To examine whether the high levels of these isotypes in circulation are reflected in a higher capacity of PBMC to produce IgG4 and IgE, we examined cells from patients infected with filarial nematodes that exhibit high levels of IgG4 and IgE. Indeed, IgG4 production by PBMC correlated strongly with plasma levels of IgG4 (r = 0.534, P = 0.002), but such correlation was not found for IgE. The replacement of CD19+ cells from PBMC by IgD+ cells abrogated the high capacity of PBMC to make IgG4. This indicates that an altered B cell compartment accounts for the high IgG4-producing capacity of the PBMC. The high production of IgG4 in vitro was not dependent on IL-4 and IL-13, as neutralizing antibodies to these cytokines did not inhibit IgG4. However, IgE release by PBMC was dependent on IL-4 and IL-13. Anti-filarial IgG4 was detected in culture supernatants from filarial patients and its production was independent of IL-4 and IL-13. These results demonstrate that in individuals with elevated IgG4, the B cell compartment in PBMC carries cells that are already committed to IgG4 production and are independent of IL-4 and IL-13. [ABSTRACT FROM AUTHOR]

Background The classic technique used to detect hookworm infections in population-based surveys is microscopic examination of Kato thick smears of multiple faecal samples per person as variation in soil-transmitted helminth egg output is common. Methods As an alternative to this time-consuming and logistically difficult procedure, a PCR-based method to detect hookworm infections was evaluated. Faecal samples collected from 65 Ghanaian school children during February–June 2006 were examined using both techniques. Results Thirty-one children with a hookworm infection were detected by Kato examination of three faecal samples compared with 30 children detected by PCR of a single faecal sample and 39 detected by PCR of three faecal samples. Conclusion PCR provides a sensitive alternative to the conventional microscopic detection of hookworm infections. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta‐inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega‐1 (ω1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant‐produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time‐ and dose‐dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6‐deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole‐body energy expenditure, an effect also occurring in leptin receptor‐deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole‐body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6‐independent mechanism. [ABSTRACT FROM AUTHOR]

Abstract Schistosoma mansoni is a parasitic helminth that infects millions of people mostly in tropical parts of the world. Different life cycle stages of S.mansoni, that infect or develop in the human host, promote distinct immune responses and are known for their ability to modulate host immune responses. However, the molecular mechanisms through which the parasites interact with, and modulate the host immune system remain incompletely understood. Despite the well-known ability of various lipids to modulate immune responses, a comprehensive analysis of the lipidome of the different life cycle stages has not been performed. Using three complementary MS-based platforms to detect and quantify around 350 lipid species, we here characterized the lipid profiles of S. mansoni cercariae, worms and eggs, as well as extracts and excretory/secretory (ES) products of different life cycle stages of S. mansoni. We identified life cycle stage specific signatures of lipid classes of which cercariae were found to have the most distinct profile. Moreover, we detected several immunolomodulatory oxylipids in the different life cycle stages. Specifically, prostaglandins were found to be most highly enriched in egg preparations, while resolvins were specifically detected in cercariae. Together, the generation of this detailed lipid database of the different life cycle stages of S. mansoni will not only be important for a better understanding of the biology of the parasite itself but also of host-parasite interactions and how that could result in immunomodulation. Graphical abstract Image 1 Highlights • Comprehensive Lipidomics study of Schistosoma mansoni and its life stages. • Description of a Schistosoma mansoni lipid database. • Identification of several important immunomodulatory lipids, leads for further research. [ABSTRACT FROM AUTHOR]

Abstract: Parasitic infections are common in many tropical and sub-tropical regions of the world and concomitant infection, polyparasitism, is the rule rather than the exception in such areas. At the immunological level, different parasites induce quite different responses characterised, for example, by protozoa that polarise responses towards Th1, whilst helminths are strong Th2 and regulatory T cell inducers. The question of how the co-existence of such parasites within the same host might influence the immunological responses to each species and, more importantly, whether such interactions affect resistance, susceptibility or clinical outcome, needs to be addressed in well-designed studies of sufficient power. The current paper discusses what we know as well as the gaps in our knowledge of polyparasitism. [Copyright &y& Elsevier]

SummaryBackground: Most of the effort directed at understanding the role infections have in preventing allergy has focused on bacteria and viruses and their ability to divert the immune system towards T-helper-1 responses and away from proallergic T-helper-2 responses. However, helminth infections, highly prevalent in large parts of the developing world, where allergy is uncommon, stimulate strong T-helper-2 responses. We investigated the influence of chronic helminth infections on the prevalence of atopy and aimed to understand the relation at a detailed immunological level.Methods: 520 Gabonese schoolchildren were tested for skin reaction to house-dust mite and other allergens, for Schistosoma haematobium eggs in urine, and for microfilariae in blood samples. Total and mite-specific IgE antibodies were measured. A subsample selected on the basis of their skin test to house-dust mite received detailed immunological investigations.Findings: Children with urinary schistosomiasis had a lower prevalence of a positive skin reaction to house-dust mite than those free of this infection (odds ratio 0.32 [95% CI 0.16-0.63]). The degree of sensitisation to house-dust mite could not explain this difference in skin-prick positivity. Schistosome-antigen-specific concentrations of interleukin-10 were significantly higher in infected children, and higher specific concentrations of this anti-inflammatory cytokine were negatively associated with the outcome of skin-test reactivity to mite (0.53 [0.30-0.96]). No association between polyclonal IgE antibodies and skin-test results was found.Interpretation: The anti-inflammatory cytokine, interleukin-10, induced in chronic schistosomiasis, appears central to suppressing atopy in African children. [ABSTRACT FROM AUTHOR]