Myocarditis

Deficient Regulatory T Cell Activity and Low Frequency of IL-17-Producing T Cells Correlate with the Extent of Cardiomyopathy in Human Chagas' Disease

by Fredy RS Gutierrez

BACKGROUND:
Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and... more BACKGROUND:
Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease.
METHODOLOGY/PRINCIPAL FINDINGS:
First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500).
CONCLUSION/SIGNIFICANCE:
These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.

Factors associated with posttraumatic growth among the spouses of myocardial infarction patients

by Mithat Durak

Key Words: cognitive processing, environmental factors, individual factors, myocardial infarction patients, posttraumatic growth, spouses of myocardial infarction patients

To clarify the rationale behind Posttraumatic Growth (PTG), a model by Schaefer and Moos describes the relative... more To clarify the rationale behind Posttraumatic Growth (PTG), a model by Schaefer and Moos describes the relative contribution of environmental resources, individual resources, event related factors, cognitive processing and coping (CPC) on PTG. In the present study, this model was tested with the spouses of myocardial infarction patients with data from various hospitals in Turkey. A structural equation model revealed that neither individual nor environmental resources had indirect effects on PTG through the effect of event-related factors and CPC, while they showed direct effects on PTG. The findings were discussed in the context of the theoretical model.

Factors Associated with Posttraumatic Growth Among Myocardial Infarction Patients: Perceived Social Support, Perception of the Event and Coping

by Mithat Durak

Key Words: Posttraumatic growth, Perceived social support, Perception of the event, Coping, Myocardial infarction patients

Posttraumatic Growth (PTG) is accepted as positive transformations that are a product of struggling with significant... more Posttraumatic Growth (PTG) is accepted as positive transformations that are a product of struggling with significant stressors such as chronic illness. A model, conceptualized by Schaefer and Moos (Posttraumatic growth: Positive changes in the aftermath of crisis, pp 99–126, 1998), suggests a relative contribution of environmental and individual resources, perception of the event (PE) and coping in the development of PTG. The aim of the present study was to examine the effect of perceived social support (PSS), PE and coping on PTG. This model was tested in a sample of patients with myocardial infarction (MIP, N = 148) from various hospitals in Turkey. The structural equation analysis of the model revealed that PSS was significantly related to PTG through the effect of coping. While coping was significantly and directly related to PTG, PE was not. The findings are discussed in the context of the theoretical model with suggestions for future research.

Molecular Markers for the clinical forms of Chagas Disease

by Fredy RS Gutierrez

To Cite this paper:
Guedes PMM, Gutierrez, FR, Silva GK, Silva JS. Molecular Markers for the clinical forms of Chagas Disease. Rev.Bras Med Trop v42 Supp II, 2009.

The immunological mechanisms that control the evolution of Chagas' disease are not clear, despite of a better... more The immunological mechanisms that control the evolution of Chagas' disease are not clear, despite of a better understanding of the mechanisms responsible for the genesis of the cardiac and digestive lesions.Several hypothesis have been proposed in an attempt to explain these phenomena. IN this review we discuss the participation of cytokines,c hemokines, matrix metalloproteinases, nitric oxide, costimulatory molecules, regulatory T cells, and the novel adaptive T helper response Th17 in determining clinical forms of Chagas disease.

Increased activities of cardiac matrix metalloproteinases (MMP)-2 and MMP-9 are associated with mortality during the acute phase of experimental Trypanosoma cruzi infection.

by Fredy RS Gutierrez

Gutierrez FR, Lalu MM, Mariano FS, Milanezi CM, Cena J, Gerlach RF, Santos JE, Torres-Dueñas D, Cunha FQ, Schulz R, Silva JS.
Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of Sao Paulo, Brazil.

The strong inflammatory reaction that occurs in the heart during the acute phase of Trypanosoma cruzi infection is... more The strong inflammatory reaction that occurs in the heart during the acute phase of Trypanosoma cruzi infection is modulated by cytokines and chemokines produced by leukocytes and cardiomyocytes. Matrix metalloproteinases (MMPs) have recently emerged as modulators of cardiovascular inflammation. In the present study we investigated the role of MMP-2 and MMP-9 in T. cruzi-induced myocarditis, by use of immunohistochemical analysis, gelatin zymography, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction to analyze the cardiac tissues of T. cruzi-infected C57BL/6 mice. Increased transcripts levels, immunoreactivity, and enzymatic activity for MMP-2 and MMP-9 were observed by day 14 after infection. Mice treated with an MMP inhibitor showed significantly decreased heart inflammation, delayed peak in parasitemia, and improved survival rates, compared with the control group. Reduced levels of cardiac tumor necrosis factor-alpha, interferon-gamma, serum nitrite, and serum nitrate were also observed in the treated group. These results suggest an important role for MMPs in the induction of T. cruzi-induced acute myocarditis.

Complexation of the anti-Trypanosoma cruzi drug benznidazole improves solubility and efficacy.

by Fredy RS Gutierrez

Nogueira Silva JJ, Pavanelli WR, Gutierrez FR, Alves Lima FC, Ferreira da Silva AB, Santana Silva J, Wagner Franco D.
Departamento de Quimica e Fisica Molecular, Instituto de Quimica de Sao Carlos, Universidade de Sao Paulo (USP), Sao Carlos, SP, Brazil.

The ruthenium complex, trans-[Ru(Bz)(NH 3) 4SO 2](CF 3SO 3) 2 1, Bz = benznidazole ( N-benzyl-2-(2-nitro-1... more The ruthenium complex, trans-[Ru(Bz)(NH 3) 4SO 2](CF 3SO 3) 2 1, Bz = benznidazole ( N-benzyl-2-(2-nitro-1 H-imidazol-1-yl)acetamide), is more hydrosoluble and more active (IC 50try/1 h = 79 +/- 3 microM) than free benznidazole 2 (IC 50try/1 h > 1 mM). 1 also exhibits low acute toxicity in vitro (IC 50macrophages > 1 mM) and in vivo (400 micromol/kg < LD 50 < 600 micromol/kg) and the formation of hydroxylamine is more favorable in 1 than in 2 by 9.6 kcal/mol. In murine acute models of Chagas' disease, 1 was more active than 2 even when only one dose was administrated. Moreover, 1 at a thousand-fold smaller concentration than the considered optimal dose for 2 (385 micromol/kg/day = 100 mg/kg/day), proved to be sufficient to protect all infected mice, eliminating the amastigotes in their hearts and skeletal muscles as observed in H&E micrographics.

The role of parasite persistence in pathogenesis of Chagas heart disease.

by Fredy RS Gutierrez

Gutierrez FR, Guedes PM, Gazzinelli RT, Silva JS.
Source

Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil.
Abstract

Chagas disease (CD) is caused by the infection with the protozoan haemoflagellate Trypanosoma cruzi. This disease is... more Chagas disease (CD) is caused by the infection with the protozoan haemoflagellate Trypanosoma cruzi. This disease is still a great menace to public health, and is largely neglected as it affects mostly the poorest populations of Latin America. Nonetheless, there are neither effective diagnostic markers nor therapeutic options to accurately detect and efficiently cure this chronic infection. In spite of the great advances in the knowledge of the biology of natural transmission, as well as the immunobiology of the host-parasite interaction, the understanding of the pathogenesis of CD remains largely elusive. In the recent decades, a controversy in the research community has developed about the relevance of parasite persistence or autoimmune phenomena in the development of chronic cardiac pathology. One of the most notable aspects of chronic CD is the progressive deterioration of cardiac function, derived mostly from structural derangement, as a consequence of the intense inflammatory process. Here we review the evidence supporting the multifactorial nature of Chagas heart disease comprising pathogen persistence and altered host immunoregulatory mechanisms.

Regulation of Trypanosoma cruzi-induced myocarditis by programmed death cell receptor 1.

by Fredy RS Gutierrez

Gutierrez FR, Mariano FS, Oliveira CJ, Pavanelli WR, Guedes PM, Silva GK, Campanelli AP, Milanezi CM, Azuma M, Honjo T, Teixeira MM, Aliberti JC, Silva JS.
Infect Immun. 2011 May;79(5):1873-81. Epub 2011 Feb 28.

Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction.... more Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1(-/-) mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.

Current status of Chagas disease chemotherapy.

by Fredy RS Gutierrez

Guedes PM, Silva GK, Gutierrez FR, Silva JS.
Expert Rev Anti Infect Ther. 2011 May;9(5):609-20.

Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic... more Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.

Cutting edge: nucleotide-binding oligomerization domain 1-dependent responses account for murine resistance against Trypanosoma cruzi infection

by Fredy RS Gutierrez

Silva GK, Gutierrez FR, Guedes PM, Horta CV, Cunha LD, Mineo TW, Santiago-Silva J, Kobayashi KS, Flavell RA, Silva JS, Zamboni DS.
Department of Cell Biology, University of São Paulo, School of Medicine Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.

An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host... more An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host resistance against Chagas disease, a severe and chronic illness that affects millions of people in Latin America. In this study, we evaluated the participation of nucleotide-binding oligomerization domain (Nod)-like receptor proteins in host response to T. cruzi infection and found that Nod1-dependent, but not Nod2-dependent, responses are required for host resistance against infection. Bone marrow-derived macrophages from Nod1(-/-) mice showed an impaired induction of NF-kappaB-dependent products in response to infection and failed to restrict T. cruzi infection in presence of IFN-gamma. Despite normal cytokine production in the sera, Nod1(-/-) mice were highly susceptible to T. cruzi infection, in a similar manner to MyD88(-/-) and NO synthase 2(-/-) mice. These studies indicate that Nod1-dependent responses account for host resistance against T. cruzi infection by mechanisms independent of cytokine production.

The involvement of CD4+ CD25+ T cells in the acute phase of Trypanosoma cruzi infection

by Fredy RS Gutierrez

Mariano FS, Gutierrez FR, Pavanelli WR, Milanezi CM, Cavassani KA, Moreira AP, Ferreira BR, Cunha FQ, Cardoso CR, Silva JS.

Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes 3900, Ribeirão Preto, SP, Brazil.

The infection with Trypanosoma cruzi leads to a vigorous and apparently uncontrolled inflammatory response in the... more The infection with Trypanosoma cruzi leads to a vigorous and apparently uncontrolled inflammatory response in the heart. Although the parasites trigger specific immune response, the infection is not completely cleared out, a phenomenon that in other parasitic infections has been attributed to CD4+CD25+ T cells (Tregs). Then, we examined the role of natural Tregs and its signaling through CD25 and GITR in the resistance against infection with T. cruzi. Mice were treated with mAb against CD25 and GITR and the parasitemia, mortality and heart pathology analyzed. First, we demonstrated that CD4+CD25+GITR+Foxp3+ T cells migrate to the heart of infected mice. The treatment with anti-CD25 or anti-GITR resulted in increased mortality of these infected animals. Moreover, the treatment with anti-GITR enhanced the myocarditis, with increased migration of CD4+, CD8+, and CCR5+ leukocytes, TNF-alpha production, and tissue parasitism, although it did not change the systemic nitric oxide synthesis. These data showed a limited role for CD25 signaling in controlling the inflammatory response during this protozoan infection. Also, the data suggested that signaling through GITR is determinant to control of the heart inflammation, parasite replication, and host resistance against the infection.

The effects of nitric oxide on the immune system during Trypanosoma cruzi infection

by Fredy RS Gutierrez

Gutierrez FR, Mineo TW, Pavanelli WR, Guedes PM, Silva JS.
Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.

Trypanosoma cruzi infection triggers substantial production of nitric oxide (NO), which has been shown to have... more Trypanosoma cruzi infection triggers substantial production of nitric oxide (NO), which has been shown to have protective and toxic effects on the host's immune system. Sensing of trypomastigotes by phagocytes activates the inducible NO-synthase (NOS2) pathway, which produces NO and is largely responsible for macrophage-mediated killing of T. cruzi. NO is also responsible for modulating virtually all steps of innate and adaptive immunity. However, NO can also cause oxidative stress, which is especially damaging to the host due to increased tissue damage. The cytokines IFN-gamma and TNF-alpha, as well as chemokines, are strong inducers of NOS2 and are produced in large amounts during T. cruzi acute infection. Conversely, TGF-beta and IL-10 negatively regulate NO production. Here we discuss the recent evidence describing the mechanisms by which NO is able to exert its antimicrobial and immune regulatory effects, the mechanisms involved in the oxidative stress response during infection and the implications of NO for the development of therapeutic strategies against T. cruzi.

Nitric oxide donor trans‐[RuCl ([15] aneN4) NO] 2+ as a possible therapeutic approach for Chagas' disease

by Fredy RS Gutierrez

Guedes PM, Oliveira FS, Gutierrez FR, da Silva GK, Rodrigues GJ, Bendhack LM, Franco DW, Do Valle Matta MA, Zamboni DS, da Silva RS, Silva JS.
Department of Biochemistry and Immunology, School of Medicine at Ribeirão Preto, São Paulo, Brazil.

BACKGROUND AND PURPOSE:

Benznidazole (Bz) is the therapy currently available for clinical treatment of... more BACKGROUND AND PURPOSE:

Benznidazole (Bz) is the therapy currently available for clinical treatment of Chagas' disease. However, many strains of Trypanosoma cruzi parasites are naturally resistant. Nitric oxide (NO) produced by activated macrophages is crucial to the intracellular killing of parasites. Here, we investigate the in vitro and in vivo activities against T. cruzi, of the NO donor, trans-[RuCl([15]aneN(4))NO](2+).
EXPERIMENTAL APPROACH:

Trans-[RuCl([15]aneN(4))NO](2+)was incubated with a partially drug-resistant T. cruzi Y strain and the anti-proliferative (epimastigote form) and trypanocidal activities (trypomastigote and amastigote) evaluated. Mice were treated during the acute phase of Chagas' disease. The anti-T. cruzi activity was evaluated by parasitaemia, survival rate, cardiac parasitism, myocarditis and the curative rate.
KEY RESULTS:

Trans-[RuCl([15]aneN(4))NO](2+) was 10- and 100-fold more active than Bz against amastigotes and trypomastigotes respectively. Further, trans-[RuCl([15]aneN(4))NO](2+) (0.1 mM) induced 100% of trypanocidal activity (trypomastigotes forms) in vitro. Trans-[RuCl([15]aneN(4))NO](2+) induced permanent suppression of parasitaemia and 100% survival in a murine model of acute Chagas' disease. When the drugs were given alone, parasitological cures were confirmed in only 30 and 40% of the animals treated with the NO donor (3.33 micromol.kg(-1).day(-1)) and Bz (385 micromol.kg(-1).day(-1)), respectively, but when given together, 80% of the animals were parasitologically cured. The cured animals showed an absence of myocarditis and a normalisation of cytokine production in the sera. In addition, no in vitro toxicity was observed at the tested doses.
CONCLUSIONS AND IMPLICATIONS:

These findings indicate that trans-[RuCl([15]aneN(4))NO](2+)is a promising lead compound for the treatment of human Chagas' disease.

IL-17 produced during Trypanosoma cruzi infection plays a central role in regulating parasite-induced myocarditis

by Fredy RS Gutierrez

da Matta Guedes PM, Gutierrez FR, Maia FL, Milanezi CM, Silva GK, Pavanelli WR, Silva JS.


Department of Biochemistry and immunology, School of Medicine at Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

BACKGROUND:

Chagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi.... more BACKGROUND:

Chagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi. Around 30% of the infected patients develop chronic cardiomyopathy or megasyndromes, which are high-cost morbid conditions. Immune response against myocardial self-antigens and exacerbated Th1 cytokine production has been associated with the pathogenesis of the disease. As IL-17 is involved in the pathogenesis of several autoimmune, inflammatory and infectious diseases, we investigated its role during the infection with T. cruzi.
METHODOLOGY/PRINCIPAL FINDINGS:

First, we detected significant amounts of CD4, CD8 and NK cells producing IL-17 after incubating live parasites with spleen cells from normal BALB/c mice. IL-17 is also produced in vivo by CD4(+), CD8(+) and NK cells from BALB/c mice on the early acute phase of infection. Treatment of infected mice with anti-mouse IL-17 mAb resulted in increased myocarditis, premature mortality, and decreased parasite load in the heart. IL-17 neutralization resulted in increased production of IL-12, IFN-gamma and TNF-alpha and enhanced specific type 1 chemokine and chemokine receptors expression. Moreover, the results showed that IL-17 regulates T-bet, RORgammat and STAT-3 expression in the heart, showing that IL-17 controls the differentiation of Th1 cells in infected mice.
CONCLUSION/SIGNIFICANCE:

These results show that IL-17 controls the resistance to T. cruzi infection in mice regulating the Th1 cells differentiation, cytokine and chemokine production and control parasite-induced myocarditis, regulating the influx of inflammatory cells to the heart tissue. Correlations between the levels of IL-17, the extent of myocardial destruction, and the evolution of cardiac disease could identify a clinical marker of disease progression and may help in the design of alternative therapies for the control of chronic morbidity of chagasic patients.

The role of parasite persistence in pathogenesis of Chagas heart disease.

by Fredy RS Gutierrez

Gutierrez FR, Guedes PM, Gazzinelli RT, Silva JS.
Source

Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil.
Abstract

Chagas disease (CD) is caused by the infection with the protozoan haemoflagellate Trypanosoma cruzi. This disease is... more Chagas disease (CD) is caused by the infection with the protozoan haemoflagellate Trypanosoma cruzi. This disease is still a great menace to public health, and is largely neglected as it affects mostly the poorest populations of Latin America. Nonetheless, there are neither effective diagnostic markers nor therapeutic options to accurately detect and efficiently cure this chronic infection. In spite of the great advances in the knowledge of the biology of natural transmission, as well as the immunobiology of the host-parasite interaction, the understanding of the pathogenesis of CD remains largely elusive. In the recent decades, a controversy in the research community has developed about the relevance of parasite persistence or autoimmune phenomena in the development of chronic cardiac pathology. One of the most notable aspects of chronic CD is the progressive deterioration of cardiac function, derived mostly from structural derangement, as a consequence of the intense inflammatory process. Here we review the evidence supporting the multifactorial nature of Chagas heart disease comprising pathogen persistence and altered host immunoregulatory mechanisms.

5-Lipoxygenase is a key determinant of acute myocardial inflammation and mortality during Trypanosoma cruzi infection

by Fredy RS Gutierrez

Pavanelli WR, Gutierrez FR, Mariano FS, Prado CM, Ferreira BR, Teixeira MM, Canetti C, Rossi MA, Cunha FQ, Silva JS.
Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil.

This study provides evidence supporting the idea that although inflammatory cells migration to the cardiac tissue is... more This study provides evidence supporting the idea that although inflammatory cells migration to the cardiac tissue is necessary to control the growth of Trypanosoma cruzi, the excessive influx of such cells during acute myocarditis may be deleterious to the host. Production of lipid mediators of inflammation like leukotrienes (LTs) along with cytokines and chemokines largely influences the severity of inflammatory injury in response to tissue parasitism. T. cruzi infection in mice deficient in 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of LTs and other lipid inflammatory mediators, resulted in transiently increased parasitemia, and improved survival rate compared with WT mice. Myocardia from 5-LO(-/-) mice exhibited reduced inflammation, collagen deposition, and migration of CD4(+), CD8(+), and IFN-gamma-producer cells compared with WT littermates. Moreover, decreased amounts of TNF-alpha, IFN-gamma, and nitric oxide synthase were found in the hearts of 5-LO(-/-) mice. Interestingly, despite of early higher parasitic load, 5-LO(-/-) mice survived, and controlled T. cruzi infection. These results show that efficient parasite clearance is possible in a context of moderate inflammatory response, as occurred in 5-LO(-/-) mice, in which reduced myocarditis protects the animals during T. cruzi infection.

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