• Chagas disease
• Immune response
• Prophylactic vaccine
• Therapeutic vaccine

• IFN-γ inhibitory molecules
• chicken coccidia
• immune evasion
• innate immunity

• Animals
• Chickens
• Eimeria
• Interleukin-12/genetics
• Interleukin-12/metabolism
• Signal Transduction
• Macrophages
• RNA, Messenger/metabolism

• CK2 activity
• Host-parasite interaction
• Protein kinases
• Trypanosoma cruzi

• Animals
• Humans
• Trypanosoma cruzi/metabolism
• Casein Kinase II/metabolism
• Chagas Disease/parasitology
• Invertebrates
• Mammals

• E-26/211.845/2021 Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

• cancer
• dysbiosis
• epithelial–mesenchymal transition
• gut
• microbiota

• BALB/c
• C57BL/6
• Cytokine/chemokine
• Trichomoniasis

Climate change is increasing the risk of spreading vector-borne diseases such as African Animal Trypanosomiasis (AAT), which is causing major economic losses, especially in sub-Saharan African countries. Mainly considering this disease, we have investigated transcriptomic and genomic data from two cattle breeds, namely Boran and N‘Dama, where the former is known for its susceptibility and the latter one for its tolerance to the AAT. Despite the rich literature on this disease, there is still a need to investigate underlying genetic mechanisms to decipher the complex interplay of regulatory SNPs (rSNPs), their corresponding gene expression profiles and the downstream effectors associated with the AAT disease. The findings of this study complement our previous results, which mainly involve the upstream events, including transcription factors (TFs) and their co-operations as well as master regulators. Moreover, our investigation of significant rSNPs and effectors found in the liver, spleen and lymph node tissues of both cattle breeds could enhance the understanding of distinct mechanisms leading to either resistance or susceptibility of cattle breeds.

African Animal Trypanosomiasis (AAT) is a neglected tropical disease and spreads by the vector tsetse fly, which carries the infectious Trypanosoma sp. in their saliva. Particularly, this parasitic disease affects the health of livestock, thereby imposing economic constraints on farmers, costing billions of dollars every year, especially in sub-Saharan African countries. Mainly considering the AAT disease as a multistage progression process, we previously performed upstream analysis to identify transcription factors (TFs), their co-operations, over-represented pathways and master regulators. However, downstream analysis, including effectors, corresponding gene expression profiles and their association with the regulatory SNPs (rSNPs), has not yet been established. Therefore, in this study, we aim to investigate the complex interplay of rSNPs, corresponding gene expression and downstream effectors with regard to the AAT disease progression based on two cattle breeds: trypanosusceptible Boran and trypanotolerant N’Dama. Our findings provide mechanistic insights into the effectors involved in the regulation of several signal transduction pathways, thereby differentiating the molecular mechanism with regard to the immune responses of the cattle breeds. The effectors and their associated genes (especially MAPKAPK5, CSK, DOK2, RAC1 and DNMT1) could be promising drug candidates as they orchestrate various downstream regulatory cascades in both cattle breeds.

• Chagas disease
• TGF-beta
• biomarker
• fibrosis
• polymorphism

• Animals
• Biomarkers
• Chagas Disease/parasitology
• Humans
• Immunogenetics
• Mice
• Transforming Growth Factor beta/metabolism
• Trypanosoma cruzi/metabolism

• Ministério da Saúde
• Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

• Animals
• Humans
• Male
• Mice
• Acute Disease
• Chagas Cardiomyopathy
• Chagas Disease/immunology
• Inflammation/genetics
• Inflammation/metabolism
• Interleukins/genetics
• Interleukins/metabolism
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Animal
• Myocardium/pathology
• Parasitemia/immunology
• Trypanosoma cruzi/physiology

• Bacteria
• Cytokine
• Fungi
• Helminths
• Immunity
• Protozoa
• Virus

Resistance or susceptibility to T. cruzi infection is dependent on the host immunological profile. Innate immune receptors, such as Toll-like receptors (TLRs/TLR2, TLR4, TLR7, and TLR9) and Nod-like receptors (NLRs/NOD1 and NLRP3 inflammasome) are involved with the resistance against acute experimental T. cruzi infection. Here, we evaluated the impact of T. cruzi virulence on the expression of innate immune receptors and its products in mice. For that, we used six T. cruzi strains/isolates that showed low (AM64/TcIV and 3253/Tc-V), medium (PL1.10.14/TcIII and CL/TcVI), or high (Colombian/Tc-I and Y/TcII) virulence and pathogenicity to the vertebrate host and belonging to the six discrete typing units (DTUs)—TcI to TcVI. Parasitemia, mortality, and myocarditis were evaluated and correlated to the expression of TLRs, NLRs, adapter molecules, cytokines, and iNOS in myocardium by real time PCR. Cytokines (IL-1β, IL-12, TNF-α, and IFN-γ) were quantified in sera 15 days after infection. Our data indicate that high virulent strains of T. cruzi, which generate high parasitemia, severe myocarditis, and 100% mortality in infected mice, inhibit the expression of TLR2, TLR4, TLR9, TRIF, and Myd88 transcripts, leading to a low IL-12 production, when compared to medium and low virulent T. cruzi strains. On the other hand, the high virulent T. cruzi strains induce the upregulation of NLRP3, caspase-1, IL-1β, TNF-α, and iNOS mRNA in heart muscle, compared to low and medium virulent strains, which may contribute to myocarditis and death. Moreover, high virulent strains induce higher levels of IL-1β and TNF-α in sera compared to less virulent parasites. Altogether the data indicate that differential TLR and NLR expression in heart muscle is correlated with virulence and pathogenicity of T cruzi strains. A better knowledge of the immunological mechanisms involved in resistance to T. cruzi infection is important to understand the natural history of Chagas disease, can lead to identification of immunological markers and/or to serve as a basis for alternative therapies.

• NLRP3 inflammasome
• Nod-like receptor
• Toll-like receptor
• Trypanosoma cruzi
• innate immune receptors
• mice
• virulence

Malarial disease caused by Plasmodium parasites challenges the mammalian immune system with a delicate balancing act. Robust inflammatory responses are required to control parasite replication within red blood cells, which if unchecked, can lead to severe anemia and fatality. However, the same inflammatory response that controls parasite replication is also associated with immunopathology and severe disease, as is exemplified by cerebral malaria. A robust literature has identified critical roles for innate, cellular, and humoral immune responses orchestrated by IFN-γ and T_H1 type responses in controlling blood stage malarial disease. In contrast, TGF-β and IL-10 have been identified as important anti–inflammatory immunomodulators that help to limit inflammation and pathology during malaria. TGF-β is a pleiotropic cytokine, with the ability to exert a wide variety of context-dependent immunomodulatory roles.

The specific mechanisms that allow TGF-β to protect against malarial pathology remain essentially unexplored and offer a promising avenue to dissect the most critical elements of immunomodulation in avoiding severe malaria. Here we discuss potential immunomodulatory roles for TGF-β during malaria in light of recent advances in our understanding of the role of Tregs during blood-stage malaria.

• Malaria
• TGF-β
• inflammation

• Chronic chagasic cardiomyopathy
• PI3Kγ gene
• Single nucleotide polymorphism
• Trypanosoma cruzi

Cardiopathy is a common, irreversible manifestation of the chronic phase of Chagas disease; however, there is controversy as to how the causes for progression from the acute to the chronic phase are defined. In this work, the presence of the parasite is correlated with the occurrence of cell infiltration and fibrosis in cardiac tissues, as well as IgG detection and disease progression in a murine model. Fifty CD1 mice were infected intraperitoneally with Trypanosoma cruzi, while 30 control were administered with saline solution. Parasitemia levels were determined, and IgG titers were quantified by ELISA. At different times, randomly selected mice were euthanized, and the heart was recovered. Cardiac tissue slides were stained with HE and Masson trichrome stain. A significant increase in parasitemia levels was observed after 15 days post-infection (dpi), with a maximum of 4.1 × 10⁶ parasites on 33 dpi, ending on 43 dpi; amastigote nests were observed on 15–62 dpi. Histological analysis revealed lymphocytic infiltration and fibrotic lesions from 8 dpi until the end of the study, on 100 dpi. The presence of plasma cells in the myocardium observed on 40–60 dpi, accompanied by seropositivity to ELISA on 40–100 dpi, was regarded as the hallmark of the transition phase. Meanwhile, the chronic phase, characterized by the absence of amastigotes, presence of cell infiltration, fibrotic lesions, and seropositivity, started on 62 dpi. A strong correlation between parasitemia and the presence of amastigote nests was found (r² = 0.930), while correlation between the presence of fibrosis and of amastigote nests was weak (r² = 0.306), and that between fibrosis and lymphocyte infiltration on 100 dpi was strong (r² = 0.899). The murine model is suitable to study Chagas disease, since it can reproduce the chronic and acute phases of the human disease. The acute phase was determined to occur on 1–60 dpi, while the chronic phase starts on 62 dpi, and fibrotic damage is a consequence of the continuous inflammatory infiltration; on the other hand, fibrosis was determined to start on the acute phase, being more apparent in the chronic phase, when Chagas disease-related cardiopathy is induced.

• Chagas disease
• Trypanosoma cruzi
• cardiopathy
• histopathology
• murine model

• Cardiac fibrosis
• Cardiac microtissues
• Chagas disease
• Extracellular matrix protein
• Posaconazole
• Three-dimensional culture

• Animals
• Cell Culture Techniques
• Chagas Cardiomyopathy/drug therapy
• Chagas Cardiomyopathy/genetics
• Chagas Cardiomyopathy/parasitology
• Chagas Cardiomyopathy/pathology
• Endomyocardial Fibrosis/drug therapy
• Endomyocardial Fibrosis/genetics
• Endomyocardial Fibrosis/parasitology
• Endomyocardial Fibrosis/pathology
• Extracellular Matrix Proteins/genetics
• Extracellular Matrix Proteins/metabolism
• Fetus
• Fibronectins/genetics
• Fibronectins/metabolism
• Gene Expression Regulation
• Humans
• Inhibitory Concentration 50
• Laminin/genetics
• Laminin/metabolism
• Mice
• Models, Biological
• Myocytes, Cardiac/drug effects
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/parasitology
• Parasite Load
• Primary Cell Culture
• Tissue Inhibitor of Metalloproteinases/genetics
• Tissue Inhibitor of Metalloproteinases/metabolism
• Transforming Growth Factor beta/genetics
• Transforming Growth Factor beta/metabolism
• Triazoles/pharmacology
• Trypanocidal Agents/pharmacology
• Trypanosoma cruzi/drug effects
• Trypanosoma cruzi/growth & development
• Trypanosoma cruzi/pathogenicity
• Tissue Inhibitor of Metalloproteinase-4

A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-β are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibrosis upon infection with Trypanosoma cruzi. Thus, considering that the heart is one of the main target organs in Chagas disease, knowledge regarding the mechanisms of action of these molecules is essential to understand how they interact and trigger local and systemic reactions and, consequently, determine whether they contribute to the development of Chagas' heart disease. In this sense, it is believed that the inflammatory microenvironment caused by the infection alters the expression of these proteins favoring progression of the host-parasite cycle and thereby stimulating cardiac tissue remodeling mechanisms and fibrosis. The aim of this review was to gather information on metalloproteinases and their tissue inhibitors, galectins, and TGF-β and discuss how these molecules and their different interrelationships contribute to the development of Chagas' heart disease.

Dendritic cells (DCs) are a type of antigen-presenting cells that play an important role in the immune response against Trypanosoma cruzi, the causative agent of Chagas disease. In vitro and in vivo studies have shown that the modulation of these cells by this parasite can directly affect the innate and acquired immune response of the host in order to facilitate its biological cycle and the spreading of the species. Many studies show the mechanisms by which T. cruzi modulates DCs, but the interaction of these cells with the Mexican strains of T. cruzi such as Ninoa and INC5 has not yet been properly investigated. Here, we evaluated whether Ninoa and INC5 strains evaded the immunity of their hosts by modulating the biology and function of murine DCs. The CL-Brener strain was used as the reference strain. Herein, it was demonstrated that Ninoa was more infective toward bone marrow-derived dendritic cells (BMDCs) than INC5 and CL-Brener strains in both BMDCs of BALB/c and C57BL/6 mice. Mexican strains of T. cruzi induced different cytokine patterns. In BMDCs obtained from BALB/c mice, Ninoa strain led to the reduction in IL-6 and increased IL-10 production, while in C57BL/6 mice Ninoa strain considerably increased the productions of TNF-α and IL-10. Also, Ninoa and INC5 differentially modulated BMDC expressions of MHC-II, TLR2, and TLR4 in both BALB/c and C57BL/6 mice compared to Brazilian strain CL-Brener. These results indicate that T. cruzi Mexican strains differentially infect and modulate MHC-II, toll-like receptors, and cytokine production in DCs obtained from C57BL/6 and BALB/c mice, suggesting that these strains have developed particular modulatory strategies to disrupt DCs and, consequently, the host immune responses.

• Clinical symptoms
• Controlled human malaria infection
• Haemostasis
• Heterogeneity
• TGF-β

• Animals
• Benzamides/therapeutic use
• Chagas Cardiomyopathy/drug therapy
• Chagas Cardiomyopathy/parasitology
• Chagas Cardiomyopathy/pathology
• Chronic Disease
• Connexin 43/metabolism
• Disease Models, Animal
• Female
• Fibrosis/drug therapy
• Heart/drug effects
• Heart/parasitology
• Heart Conduction System/drug effects
• Mice
• Mice, Inbred C57BL
• Parasite Load
• Pyrazoles/therapeutic use
• Transforming Growth Factor beta/antagonists & inhibitors
• Trypanocidal Agents/therapeutic use
• Trypanosoma cruzi/drug effects

• FAPERJ
• CNPq
• Fundação Oswaldo Cruz

• Chemokines
• Cutaneous leishmaniasis
• Cytokines
• Genetic-variant strains
• L. braziliensis

• Chagas disease
• Human African Trypanosomiasis
• host-directed therapy
• leishmaniasis
• treatment

Inflammatory response in Chagas disease is related to parasite and host factors. However, immune system regulation has not been fully elucidated. Thus, this study is aimed at evaluating IL-4 influence on acute phase of Trypanosoma cruzi experimental infection through dosage of cytokine levels in cardiac homogenate of infected Balb/c WT and Balb/c IL-4^−/− as well as its histopathological repercussions. For such purpose, mice were divided into two groups: an infected group with 100 forms of the Colombian strain and an uninfected group. After 21 days of infection, animals were euthanized and the blood, spleen, and heart were collected. The spleen was used to culture splenic cells in 48 h. Subsequently, cytokines TNF-α, IL-12p70, IL-10, IFN-γ, and IL-17 were measured in the blood, culture supernatant, and heart apex by ELISA. The base of the heart was used for histopathological analysis. From these analysis, infected Balb/c IL-4^−/− mice showed milder inflammatory infiltrate compared to Balb/c WT, but without changes in nest density and collagen deposition. IL-4 absence culminated in lower cardiac tissue IFN-γ production, although it did not affect TNF-α expression in situ. It also decreased TNF-α systemic production and increased IL-10, both systemically and in situ. In addition, IL-4 absence did not influence IL-17 expression. Splenocytes of IL-4-deficient mice produced higher amounts of IFN-γ, TNF-α, and IL-17 and lower amounts of IL-10. Thus, IL-4 absence in acute phase of experimental infection with T. cruzi Colombian strain reduces myocarditis due to lower IFN-γ production and greater IL-10 production in situ and this pattern is not influenced by splenocyte general repertoire.

• Citrobacter
• Salmonella
• Smad

Trypanosoma cruzi is the etiologic agent of Chagas’ disease, which affects 6–7 million people worldwide. Different strains of T. cruzi present specific genotypic and phenotypic characteristics that affect the host–pathogen interactions, and thus, the parasite has been classified into six groups (TcI to TcVI). T. cruzi infection presents two clinical phases, acute and chronic, both with distinct characteristics and important participation by the immune system. However, the specific contributions of parasite and host factors in the disease phases are not yet fully understood. The murine model for Chagas’ disease is well-established and reproduces important features of the human infection, providing an experimental basis for the study of host lineages and parasite strains. Thus, we evaluated acute and chronic infection by the G (TcI) and CL (TcVI) strains of T. cruzi, which have distinct tropisms and infectivity, in two inbred mice lineages (C57BL/6 and BALB/c) that display variable degrees of susceptibility to different T. cruzi strains. Analysis of the parasite loads in host tissues by qPCR showed that CL strain established an infection faster than the G strain; at the same time, the response in BALB/c mice, although diverse in terms of cytokine secretion, was initiated earlier than that in C57BL/6 mice. At the parasitemia peak in the acute phase, we observed, either by confocal microscopy or by qPCR, that the infection was disseminated in all groups analyzed, with some differences concerning parasite tropism; at this point, all animals responded to infection by increasing the serum concentrations of cytokines. However, BALB/c mice seemed to better regulate the immune response than C57BL/6 mice. Indeed, in the chronic phase, C57BL/6 mice still presented exacerbated cytokine and chemokine responses. In summary, our results indicate that in these experimental models, the deregulation of immune response that is typical of chronic Chagas’ disease may be due to control loss over pro- and anti-inflammatory cytokines early in the acute phase of the disease, depending primarily on the host background rather than the parasite strain.

• Chagas’ disease
• Trypanosoma cruzi
• cytokines
• immune response
• mice

• chagas disease
• immune response
• immunoregulation
• innate immunity
• monocytes

Chagas disease is a multisystemic disorder caused by the protozoan parasite Trypanosoma cruzi, which affects ~8 million people in Latin America, killing 7,000 people annually. Chagas disease is one of the main causes of death in the endemic area and the leading cause of infectious myocarditis in the world. T. cruzi infection induces two phases, acute and chronic, where the infection is initially asymptomatic and the majority of patients will remain clinically indeterminate for life. However, over a period of 10–30 years, ~30% of infected individuals will develop irreversible, potentially fatal cardiac syndromes (chronic chagasic cardiomyopathy [CCC]), and/or dilatation of the gastro-intestinal tract (megacolon or megaesophagus). Myocarditis is the most serious and frequent manifestation of chronic Chagas heart disease and appears in about 30% of infected individuals several years after infection occurs. Myocarditis is characterized by a mononuclear cell infiltrate that includes different types of myeloid and lymphoid cells and it can occur also in the acute phase. T. cruzi infects and replicates in macrophages and cardiomyocytes as well as in other nucleated cells. The pathogenesis of the chronic phase is thought to be dependent on an immune-inflammatory reaction to a low-grade replicative infection. It is known that cytokines produced by type 1 helper CD4+ T cells are able to control infection. However, the role that infiltrating lymphoid and myeloid cells may play in experimental and natural Chagas disease pathogenesis has not been completely elucidated, and several reports indicate that it depends on the mouse genetic background and parasite strain and/or inoculum. Here, we review the role that T cell CD4+ subsets, myeloid subclasses including myeloid-derived suppressor cells may play in the immunopathogenesis of Chagas disease with special focus on myocarditis, by comparing results obtained with different experimental animal models.

• Chagas disease
• MDSCs
• Th1 cells
• Th17 cells
• Trypanosoma cruzi
• immunoegulation
• myocarditis
• regulatory T cells

Transforming growth factor β1 (TGF-β1) and tumour necrosis factor (TNF) have been implicated in Chagas disease pathophysiology and may correlate with left ventricular (LV) function.

We determined whether TGF-β1 and TNF serum levels correlate with LV systolic and diastolic functions and brain natriuretic peptide (BNP) serum levels in chronic Chagas disease.

This cross-sectional study included 152 patients with Chagas disease (43% men; 57 ± 12 years old), classified as 53 patients with indeterminate form and 99 patients with cardiac form (stage A: 24, stage B: 25, stage C: 44, stage D: 6). TGF-β1, TNF, and BNP were determined by enzyme-linked immunosorbent assay ELISA. Echocardiogram was used to determine left atrial and LV diameters, as well as LV ejection fraction and diastolic function.

TGF-b1 serum levels were lower in stages B, C, and D, while TNF serum levels were higher in stages C and D of the cardiac form. TGF-β1 presented a weak correlation with LV diastolic function and LV ejection fraction. TNF presented a weak correlation with left atrial and LV diameters and LV ejection fraction.

TNF is increased, while TGF-β1 is decreased in the cardiac form of chronic Chagas disease. TNF and TGF-β1 serum levels present a weak correlation with LV systolic and diastolic function in Chagas disease patients.

• Host metabolic landscape
• Host metabolic pathways
• Host–parasite interaction
• Nutrient sensing pathways
• Scavenging of nutrients

• Animals
• Host-Pathogen Interactions
• Metabolic Networks and Pathways
• Nutritional Physiological Phenomena
• Parasites/metabolism

• Chagas disease
• Cytokines
• Immune response
• Trypanosoma cruzi
• q-PCR

• Trypanosoma cruzi
• chagas disease
• dogs
• immunomodulation
• infection model
• macrophages
• susceptibility

• Encephalitis
• Inflammatory infiltrates
• Myocarditis
• Toxoplasmosis

• Chagas disease
• biomarkers for immune responsiveness
• clinical forms
• human experimentation
• mini review

Chagas disease is a serious illness caused by the protozoan parasite Trypanosoma cruzi. Nearly 30% of chronically infected people develop cardiac, digestive, or mixed alterations, suggesting a broad range of host-parasite interactions that finally impact upon chronic disease outcome. The ability of T. cruzi to persist and cause pathology seems to depend on diverse factors like T. cruzi strains, the infective load and the route of infection, presence of virulence factors, the parasite capacity to avoid protective immune response, the strength and type of host defense mechanisms and the genetic background of the host. The host-parasite interaction is subject to a constant neuro-endocrine regulation that is thought to influence the adaptive immune system, and as the infection proceeds it can lead to a broad range of outcomes, ranging from pathogen elimination to its continued persistence in the host. In this context, T. cruzi evasion strategies and host defense mechanisms can be envisioned as two sides of the same coin, influencing parasite persistence and different outcomes observed in Chagas disease. Understanding how T. cruzi evade host's innate and adaptive immune response will provide important clues to better dissect mechanisms underlying the pathophysiology of Chagas disease.

• Chagas disease
• evasion strategies
• immunoendocrine
• persistence
• thymus
• virulence factors

Trypanosoma cruzi strains are currently classified into six discrete typing units (DTUs) named TcI to VI. It is known that these DTUs have different geographical distribution, as well as biological features. TcI and TcII are major DTUs found in patients from northern and southern Latin America, respectively. Our hypothesis is that upon infection of human peripheral blood cells, Y strain (Tc II) and Col cl1.7 (Tc I), cause distinct immunological changes, which might influence the clinical course of Chagas disease.

We evaluated the infectivity of CFSE-stained trypomastigotes of Col cl1.7 and Y strain in human monocytes for 15 and 72 hours, and determined the immunological profile of lymphocytes and monocytes exposed to the different isolates using multiparameter flow cytometry. Our results showed a similar percentage and intensity of monocyte infection by Y and Col cl1.7. We also observed an increased expression of CD80 and CD86 by monocytes infected with Col cl1.7, but not Y strain. IL-10 was significantly higher in monocytes infected with Col cl1.7, as compared to Y strain. Moreover, infection with Col cl1.7, but not Y strain, led to an increased expression of IL-17 by CD8+ T cells. On the other hand, we observed a positive correlation between the expression of TNF-alpha and granzyme A only after infection with Y strain.

Our study shows that while Col cl1.7 induces higher monocyte activation and, at the same time, production of IL-10, infection with Y strain leads to a lower monocyte activation but higher inflammatory profile. These results show that TcI and TcII have a distinct immunological impact on human cells during early infection, which might influence disease progression.

Chagas disease remains a major public health problem in Latin America with over 13 million people infected. It is believed that the host immune response and genetic diversity of the parasite play an important role in the progression of Chagas disease, which presents a variety of clinical forms ranging from indeterminate to cardiac and digestive forms. Since parasite genetic diversity may influence the development of Chagas disease, our study aims to understand the immune response of human peripheral blood cells upon infection with two T. cruzi strains with different genetic backgrounds (Col cl1.7 – Tc I, and Y strain – TcII). Our study showed differences in the expression of cytokines and activation molecules between cells infected with strains from Tc I (Col cl1.7) and Tc II (Y strain). These data show the importance of parasite strain in the development of the host response early in infection, which may influence the clinical progression of Chagas disease.

• Adult
• Chagas Disease/immunology
• Chagas Disease/parasitology
• Female
• Humans
• Interleukin-10/immunology
• Lymphocyte Activation
• Lymphocytes/immunology
• Male
• Monocytes/immunology
• Trypanosoma cruzi/physiology
• Young Adult

• Candida albicans
• ELISA
• cytokines
• cytometric bead array analysis

Trypanosoma cruzi is the causative agent of Chagas disease. Approximately 8 million people are thought to be affected worldwide. Several players in host lipid metabolism have been implicated in T. cruzi-host interactions in recent research, including macrophages, adipocytes, low density lipoprotein (LDL), low density lipoprotein receptor (LDLR), and high density lipoprotein (HDL). All of these factors are required to maintain host lipid homeostasis and are intricately connected via several metabolic pathways. We reviewed the interaction of T. cruzi with each of the relevant host components, in order to further understand the roles of host lipid metabolism in T. cruzi infection. This review sheds light on the potential impact of T. cruzi infection on the status of host lipid homeostasis.

Chagas disease cardiomyopathy (CCC), the main consequence of Trypanosoma cruzi (T.cruzi) infection, is an inflammatory cardiomyopathy that develops in up to 30% of infected individuals. The heart inflammation in CCC patients is characterized by a Th1 T cell-rich myocarditis with increased production of interferon (IFN)-γ, produced by the CCC myocardial infiltrate and detected at high levels in the periphery. IFN-γ has a central role in the cardiomyocyte signaling during both acute and chronic phases of T.cruzi infection. In this review, we have chosen to focus in its pleiotropic mode of action during CCC, which may ultimately be the strongest driver towards pathological remodeling and heart failure. We describe here the antiparasitic protective and pathogenic dual role of IFN-γ in Chagas disease.

• Chagas disease
• Trypanosoma cruzi
• Interferon-gamma
• Gene expression
• Cardiomyopathy

• Animals
• Chagas Cardiomyopathy/genetics
• Chagas Cardiomyopathy/immunology
• Chagas Cardiomyopathy/metabolism
• Chagas Cardiomyopathy/pathology
• Humans

• IL-10
• IL-27
• cytokine
• immune regulation
• immunopathology
• parasite

• BT
• Chagas disease
• Chemokine receptor
• Chemokines
• Cytokines
• GAPDH
• GPI
• IFN-γ
• IL-10
• IL-12
• IL-4
• MIP
• MT
• NI
• RA
• TGF-β
• Trypanosoma cruzi
• UFOP
• Universidade Federal de Ouro Preto
• blood trypomastigotes
• glyceraldehyde-3-phosphate dehydrogenase
• glycosylphosphatidylinositol
• interferon-gamma
• interleukin-10
• interleukin-12
• interleukin-4
• macrophage inflammatory protein
• metacyclic trypomastigotes
• not infected
• right atrium
• transforming growth factor β

Trypanosoma cruzi (T. cruzi) infection produces an intense inflammatory response which is critical for the control of the evolution of Chagas’ disease. Interleukin (IL)-10 is one of the most important anti-inflammatory cytokines identified as modulator of the inflammatory reaction. This work shows that exogenous addition of IL-10 inhibited ERK1/2 and NF-κB activation and reduced inducible nitric oxide synthase (NOS2), metalloprotease (MMP) -9 and MMP-2 expression and activities, as well as tumour necrosis factor (TNF)-α and interleukin (IL)-6 expression, in T. cruzi-infected cardiomyocytes. We found that T. cruzi and IL-10 promote STAT3 phosphorylation and up-regulate the expression of suppressor of cytokine signalling (SOCS)-3 thereby preventing NF-κB nuclear translocation and ERK1/2 phosphorylation. Specific knockdown of SOCS-3 by small interfering RNA (siRNA) impeded the IL-10-mediated inhibition of NF-κB and ERK1/2 activation. As a result, the levels of studied pro-inflammatory mediators were restored in infected cardiomyocytes. Our study reports the first evidence that T. cruzi up- regulates SOCS-3 expression and highlights the relevance of IL-10 in the modulation of pro-inflammatory response of cardiomyocytes in Chagas’ disease.

• Chagas disease
• Echocardiography
• Heart failure
• Prognosis
• Transforming growth factor-β1