Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits.

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

WSB1 and IL21R Genetic Variants Are Involved in Th2 Immune Responses to Ascaris lumbricoides.

Genetic and epigenetic factors are considered to be critical for host-parasite interactions. There are limited data on the role of such factors during human infections with Ascaris lumbricoides. Here, we describe the potential role of genetic factors as determinants of the Th2 immune response to A. lumbricoides in Brazilian children. Stool samples were collected from the children to detect A. lumbricoides by microscopy and peripheral blood leukocytes (PBLs) were cultured in whole blood cultures for detection of cytokines (IL-5, IL-10, and IL-13) in vitro. Levels of anti-A. lumbricoides IgE and IgG4 were measured in plasma. DNA was extracted from PBLs and genotyped using Illumina 2.5 Human Omni Beadchip. Candidate genes associated with A. lumbricoides responses were identified and SNVs in these selected genes associated with the Th2 immune response to A. lumbricoides. Haplotype, gene expression, and epigenetic analyses were done to identify potential associations with Th2 immune responses. GWAS on samples from 1,189 children identified WSB1 as a candidate gene, and IL-21R was selected as a biologically relevant linked gene for further analysis. Variants in WSB1 and IL21R were associated with markers of Th2 immune responses: increased A. lumbricoides-specific IgE and IL-5/IL-13 by PBLs from infected compared to uninfected individuals. In infected children, WSB1 but not IL21R gene expression was suppressed and increased methylation was observed in the WSB1 promoter region. This is the first study to show an association between genetic variants in WSB1 and IL21R and Th2 immune responses during A. lumbricoides infections in children. WSB1/IL21R pathways could provide a potential target for the treatment of Th2-mediated diseases.

New Insights on the Zika Virus Arrival in the Americas and Spatiotemporal Reconstruction of the Epidemic Dynamics in Brazil.

Zika virus (ZIKV) became a worldwide public health emergency after its introduction in the Americas. Brazil was implicated as central in the ZIKV dispersion, however, a better understanding of the pathways the virus took to arrive in Brazil and the dispersion within the country is needed. An updated genome dataset was assembled with publicly available data. Bayesian phylogeography methods were applied to reconstruct the spatiotemporal history of ZIKV in the Americas and with more detail inside Brazil. Our analyses reconstructed the Brazilian state of Pernambuco as the likely point of introduction of ZIKV in Brazil, possibly during the 2013 Confederations Cup. Pernambuco played an important role in spreading the virus to other Brazilian states. Our results also underscore the long cryptic circulation of ZIKV in all analyzed locations in Brazil. Conclusions: This study brings new insights about the early moments of ZIKV in the Americas, especially regarding the Brazil-Haiti cluster at the base of the American clade and describing for the first time migration patterns within Brazil.

Effects of helminth co-infections on atopy, asthma and cytokine production in children living in a poor urban area in Latin America.

BACKGROUND: Helminths are modulators of the host immune system, and infections with these parasites have been associated with protection against allergies and autoimmune diseases. The human host is often infected with multiple helminth parasites and most studies to date have investigated the effects of helminths in the context of infections with single parasite or types of parasites (e.g. geohelminths). In this study, we investigated how co-infections with three nematodes affect markers of allergic inflammation and asthma in children. We selected Ascaris lumbricoides and Trichuris trichiura, two parasites that inhabit the human intestine and Toxocara spp (Toxocara canis and/or T. cati), intestinal roundworms of dogs and cats that cause systemic larval infection in humans. These parasites were selected as the most prevalent helminth parasites in our study population. RESULTS: 36.4% of children were infected with one parasite; 12.7% with 2 and 5.2% with 3. Eosinophilia>4% and >10% was present in 74.3% and 25.5% of the children, respectively. Total IgE>200 IU/mL, sIgE≥0.70 kU/L and SPT positivity were present in 59.7%, 37.1% and 30% of the children, respectively. 22.7% had recent asthma (12.0% non-atopic and 10.7% atopic). Helminth infections were associated in a dose-dependent way to decrease in the prevalence of SPT and increase in eosinophilia, total IgE, and the production of the regulatory cytokine IL-10 by unstimulated peripheral blood leukocytes. No association with asthma was observed. CONCLUSIONS: Helminth co-infections in this population were associated with increased markers of the Th2 immune response, and with a host immune regulatory phenotype that may suppress allergic effector responses such as immediate hypersensitivity reactions in the skin.

Toxocara seropositivity, atopy and wheezing in children living in poor neighbourhoods in urban Latin American.

BACKGROUND: Toxocara canis and T. cati are parasites of dogs and cats, respectively, that infect humans and cause human toxocariasis. Infection may cause asthma-like symptoms but is often asymptomatic and is associated with a marked eosinophilia. Previous epidemiological studies indicate that T. canis infection may be associated with the development of atopy and asthma. OBJECTIVES: To investigate possible associations between Toxocara spp. seropositivity and atopy and childhood wheezing in a population of children living in non-affluent areas of a large Latin American city. METHODS: The study was conducted in the city of Salvador, Brazil. Data on wheezing symptoms were collected by questionnaire, and atopy was measured by the presence of aeroallergen-specific IgE (sIgE). Skin prick test (SPT), total IgE and peripheral eosinophilia were measured. Toxocara seropositivity was determined by the presence of anti-Toxocara IgG antibodies, and intestinal helminth infections were determined by stool microscopy. FINDINGS: Children aged 4 to 11 years were studied, of whom 47% were seropositive for anti-Toxocara IgG; eosinophilia >4% occurred in 74.2% and >10% in 25.4%; 59.6% had elevated levels of total IgE; 36.8% had sIgE≥0.70 kU/L and 30.4% had SPT for at least one aeroallergen; 22.4% had current wheezing symptoms. Anti-Toxocara IgG was positively associated with elevated eosinophils counts, total IgE and the presence of specific IgE to aeroallergens but was inversely associated with skin prick test reactivity. CONCLUSION: The prevalence of Toxocara seropositivity was high in the studied population of children living in conditions of poverty in urban Brazil. Toxocara infection, although associated with total IgE, sIgE and eosinophilia, may prevent the development of skin hypersensitivity to aeroallergens, possibly through increased polyclonal IgE and the induction of a modified Th2 immune reaction.

The effect of single and multiple infections on atopy and wheezing in children.

BACKGROUND: The current epidemic of asthma and atopy has been explained by alterations in immune responses related to reduction in childhood infections. However, the findings of epidemiologic studies investigating the association between infection with atopy and asthma have been inconsistent. OBJECTIVE: We sought to investigate the effect of single or multiple infections (pathogen burden) on atopy and wheeze in urban children from Latin America. METHODS: Specific IgE against aeroallergens (sIgE) and skin prick test (SPT) reactivity for the most common local allergens were measured in 1128 children aged 4 to 11 years. Data on wheezing and potential confounders were collected by questionnaire. Infections by 8 pathogens were assessed by using serology and stool examination. Associations of wheeze and atopic outcomes with single and multiple infections were analyzed by means of logistic regression. RESULTS: Negative results for Toxoplasma gondii were associated with a higher prevalence of sIgE (≥0.70 kU/L), whereas negative results for Ascaris lumbricoides, T gondii, herpes simplex virus, and EBV were associated with a higher prevalence of SPT reactivity. Children with 3 or fewer infection markers had a higher prevalence of sIgE and SPT reactivity compared with those with 4 or more infection markers. However, isolated infections or pathogen burden were not associated with the prevalence of atopic or nonatopic wheeze. CONCLUSION: The findings provide support for the idea that the hygiene hypothesis is operating in an urban Latin American context, but its expression is thus far restricted to the atopic status of patients and not the perceived asthma symptoms.

Seroprevalence and potential risk factors for Helicobacter pylori infection in Brazilian children.

BACKGROUND: Helicobacter pylori infection has been proved to be of great relevance to public health in unindustrialized countries, especially in low socioeconomic groups. Poor hygiene, deficient sanitation, and crowded conditions have been reported as risk factors for this infection. In this work, we investigated whether social and demographic characteristics were associated with anti-H. pylori IgG antibodies in 1104 children aged 4-11 years old from Salvador, a large city located in northeastern Brazil. METHODS: Standardized questionnaires were used to obtain social, demographic, and environmental data for the studied population in two periods of time (from 1997 to 2003 and in 2005). Anti-H. pylori IgG antibodies were assessed by indirect enzyme-linked immunosorbent assay in 2005. RESULTS: Anti-H. pylori IgG antibody was present in 28.7% of the children. Among the studied variables, the following were positively associated with the presence of anti-H. pylori antibodies in multivariable analyses: age above 8 years old (OR = 1.72, 95% CI = 1.23-2.40), a larger sibling number (OR = 1.66, 95% CI = 1.26-2.18), nursery attendance (OR = 1.49, 95% CI = 1.04-2.12), location of the house at an unpaved street (OR = 2.03, 95% CI = 1.44-2.87) and absence of a flush toilet (OR = 1.32, 95% CI = 1.00-1.74). CONCLUSION: Our data show that H. pylori infection in children from a major Brazilian city is associated with variables indicative of a crowded environment and deficient sanitation/habitation conditions, leading to the conclusion that improvements in hygiene and social conditions may protect children against this infection.