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Background: Studies in murine models and human populations have indicated that the collagen-rich granulomatous response against parasite eggs trapped in the liver is associated with the development of severe hepatosplenic schistosomiasis, characterized by periportal fibrosis and portal hypertension. The role of the humoral response in parasite susceptibility has been well established, but its participation in disease severity remains poorly understood. In this work, we evaluated the relationship between parasite-reactive IgE and IgG levels and schistosomiasis morbidity in infected patients with similar parasite burdens. Methodology/Principal Findings: Ninety-seven Schistosoma mansoni-infected individuals were subjected to clinical examination and abdominal ultrasound analysis. IgG reactivity and IgE concentration against Schistosoma mansoni soluble egg antigens (SEA) and adult worm antigen preparation (SWAP) were evaluated by ELISA assay. Multivariable linear regression models were used to evaluate the relationship between parasite-reactive antibodies and the co-variables investigated. The study population showed low parasite burden (median 30 eggs/g feces), constant re-infection, and signs of fibrosis was detected in more than 30% of individuals. Most infected individuals showed IgG reactivity, and the median concentrations of IgE anti-SEA and anti-SWAP antibodies were 1,870 and 1,375 ng/mL, respectively. There was no association between parasite burden and antibody response or any parameter of disease severity. However, IgG anti-SWAP level was positively associated with morbidity parameters, such as spleen size and thickness of portal vein at the entrance and secondary branch. In contrast, the data also revealed independent inverse correlations between concentration of parasite-reactive IgE and gallbladder wall thickness, a marker of fibrosis in schistosomiasis. Conclusions/Significance: The data indicate that IgG anti-SWAP is positively associated with severe schistosomiasis, independently of parasite burden, while high production of parasite-specific IgE is associated with mild disease in the human population. Antibody profiles are good correlates for schistosomiasis severity and could be tested as biomarkers of disease severity. [ABSTRACT FROM AUTHOR]

A century after the discovery of Trypanosoma cruzi in a child living in Lassance, Minas Gerais, Brazil in 1909, many uncertainties remain with respect to factors determining the pathogenesis of Chagas disease (CD). Herein, we simultaneously investigate the contribution of both host and parasite factors during acute phase of infection in BALB/c mice infected with the JG and/or CL Brener T. cruzi strains. JG single infected mice presented reduced parasitemia and heart parasitism, no mortality, levels of pro-inflammatory mediators (TNF-α, CCL2, IL-6 and IFN-γ) similar to those found among naïve animals and no clinical manifestations of disease. On the other hand, CL Brener single infected mice presented higher parasitemia and heart parasitism, as well as an increased systemic release of pro-inflammatory mediators and higher mortality probably due to a toxic shock-like systemic inflammatory response. Interestingly, coinfection with JG and CL Brener strains resulted in intermediate parasitemia, heart parasitism and mortality. This was accompanied by an increase in the systemic release of IL-10 with a parallel increase in the number of MAC-3+ and CD4+ T spleen cells expressing IL-10. Therefore, the endogenous production of IL-10 elicited by coinfection seems to be crucial to counterregulate the potentially lethal effects triggered by systemic release of pro-inflammatory mediators induced by CL Brener single infection. In conclusion, our results suggest that the composition of the infecting parasite population plays a role in the host response to T. cruzi in determining the severity of the disease in experimentally infected BALB/c mice. The combination of JG and CL Brener was able to trigger both protective inflammatory immunity and regulatory immune mechanisms that attenuate damage caused by inflammation and disease severity in BALB/c mice. Author Summary: Chagas disease, a life-long parasitic disease caused by the flagellate protozoan Trypanosoma cruzi, was discovered a century ago by the Brazilian physician Carlos Chagas, and remains one of the most neglected tropical diseases, affecting 13 million people in Latin America. Disease is characterized by distinct clinical courses, varying from asymptomatic to severe forms with damage to heart and/or gastrointestinal tract. The causes of the different clinical manifestations are not completely understood, but they certainly involve both parasite and host features. In this study, the authors analyzed immune response of BALB/c mice to infection with two different T. cruzi populations. One of them (JG) caused low parasitism and low levels of pro-inflammatory mediators associated with no clinical manifestation of the disease. The other (CL Brener) caused severe disease, high mortality and high levels of pro-inflammatory mediators. The coinfection, however, triggered singular regulatory immune mechanism(s) that attenuated damage caused by inflammation and disease severity that are typical of the single infection with CL Brener. As mixed infection is naturally found in patients in endemic areas, these results can explain, at least in part, the complexity of the immune responses and consequently the various clinical manifestations of the disease. [ABSTRACT FROM AUTHOR]

A century after the discovery of Trypanosoma cruzi in a child living in Lassance, Minas Gerais, Brazil in 1909, many uncertainties remain with respect to factors determining the pathogenesis of Chagas disease (CD). Herein, we simultaneously investigate the contribution of both host and parasite factors during acute phase of infection in BALB/c mice infected with the JG and/or CL Brener T. cruzi strains. JG single infected mice presented reduced parasitemia and heart parasitism, no mortality, levels of pro-inflammatory mediators (TNF-α, CCL2, IL-6 and IFN-&#x03B3) similar to those found among naïve animals and no clinical manifestations of disease. On the other hand, CL Brener single infected mice presented higher parasitemia and heart parasitism, as well as an increased systemic release of pro-inflammatory mediators and higher mortality probably due to a toxic shock-like systemic inflammatory response. Interestingly, coinfection with JG and CL Brener strains resulted in intermediate parasitemia, heart parasitism and mortality. This was accompanied by an increase in the systemic release of IL-10 with a parallel increase in the number of MAC-3+ and CD4+ T spleen cells expressing IL-10. Therefore, the endogenous production of IL-10 elicited by coinfection seems to be crucial to counterregulate the potentially lethal effects triggered by systemic release of pro-inflammatory mediators induced by CL Brener single infection. In conclusion, our results suggest that the composition of the infecting parasite population plays a role in the host response to T. cruzi in determining the severity of the disease in experimentally infected BALB/c mice. The combination of JG and CL Brener was able to trigger both protective inflammatory immunity and regulatory immune mechanisms that attenuate damage caused by inflammation and disease severity in BALB/c mice. [ABSTRACT FROM AUTHOR]

Background: Chronic Chagas disease presents several different clinical manifestations ranging from asymptomatic to severe cardiac and/or digestive clinical forms. Several studies have demonstrated that immunoregulatory mechanisms are important processes for the control of the intense immune activity observed in the chronic phase. T cells play a critical role in parasite specific and non-specific immune response elicited by the host against Trypanosoma cruzi. Specifically, memory T cells, which are basically classified as central and effector memory cells, might have a distinct migratory activity, role and function during the human Chagas disease. Methodology/Principal Findings: Based on the hypothesis that the disease severity in humans is correlated to the quality of immune responses against T. cruzi, we evaluated the memory profile of peripheral CD4+ and CD8+ T lymphocytes as well as its cytokine secretion before and after in vitro antigenic stimulation. We evaluated cellular response from non-infected individuals (NI), patients with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas disease. The expression of CD45RA, CD45RO and CCR7 surface molecules was determined on CD4+ and CD8+ T lymphocytes; the pattern of intracellular cytokines (IFN-c, IL-10) synthesized by naive and memory cells was determined by flow cytometry. Our results revealed that IND and CARD patients have relatively lower percentages of naive (CD45RAhigh) CD4+ and CD8+ T cells. However, statistical analysis of ex-vivo profiles of CD4+ T cells showed that IND have lower percentage of CD45RAhigh in relation to non-infected individuals, but not in relation to CARD. Elevated percentages of memory (CD45ROhigh) CD4+ T cells were also demonstrated in infected individuals, although statistically significant differences were only observed between IND and NI groups. Furthermore, when we analyzed the profile of secreted cytokines, we observed that CARD patients presented a significantly higher percentage of CD8+CD45RAhigh IFN-c-producing cells in control cultures and after antigen pulsing with soluble epimastigote antigens. Conclusions: Based on a correlation between the frequency of IFN-c producing CD8+ T cells in the T cell memory compartment and the chronic chagasic myocarditis, we propose that memory T cells can be involved in the induction of the development of the severe clinical forms of the Chagas disease by mechanisms modulated by IFN-c. Furthermore, we showed that individuals from IND group presented more TCM CD4+ T cells, which may induce a regulatory mechanism to protect the host against the exacerbated inflammatory response elicited by the infection. [ABSTRACT FROM AUTHOR]