Immunopathological Mechanisms Underlying Cardiac Damage in Chagas Disease.

In Chagas disease, the mechanisms involved in cardiac damage are an active field of study. The factors underlying the evolution of lesions following infection by Trypanosoma cruzi and, in some cases, the persistence of its antigens and the host response, with the ensuing development of clinically observable cardiac damage, are analyzed in this review.

What Do You Need to Know before Studying Chagas Disease? A Beginner's Guide.

Chagas disease is one of the most important tropical infections in the world and mainly affects poor people. The causative agent is the hemoflagellate protozoan Trypanosoma cruzi, which circulates among insect vectors and mammals throughout the Americas. A large body of research on Chagas disease has shown the complexity of this zoonosis, and controlling it remains a challenge for public health systems. Although knowledge of Chagas disease has advanced greatly, there are still many gaps, and it is necessary to continue generating basic and applied research to create more effective control strategies. The aim of this review is to provide up-to-date information on the components of Chagas disease and highlight current trends in research. We hope that this review will be a starting point for beginners and facilitate the search for more specific information.

Tim-3 Is Differentially Expressed during Cell Activation and Interacts with the LSP-1 Protein in Human Macrophages.

T-cell Immunoglobulin and Mucin Domain 3 (TIM-3) is an immune checkpoint receptor known to regulate T-cell activation and has been targeted for immunotherapy in cancer and other diseases. However, its expression and function in other cell types, such as macrophages, are poorly understood. This study investigated TIM-3 expression in human macrophages polarized to M1 (stimulated with IFN-γ and LPS) and M2 (stimulated with IL-4 and IL-13) phenotypes using an in vitro model. Our results show that M1 macrophages have a lower frequency of TIM-3+ cells compared to M2 macrophages at 48 and 72 hr poststimulation. Additionally, we observed differential levels of soluble ADAM 10, an enzyme responsible for TIM-3 release, in the supernatants of M1 and M2 macrophages at 72 hr. We also found that the TIM-3 intracellular tail might associate with lymphocyte-specific protein 1 (LSP-1), a protein implicated in cell motility and podosome formation. These findings enhance our understanding of TIM-3 function in myeloid cells such as macrophages and may inform the development of immunotherapies with reduced immune-related adverse effects.

Changes in the Proliferation of the Neural Progenitor Cells of Adult Mice Chronically Infected with Toxoplasma gondii.

During Toxoplasma gondii chronic infection, certain internal factors that trigger the proliferation of neural progenitor cells (NPCs), such as brain inflammation, cell death, and changes in cytokine levels, are observed. NPCs give rise to neuronal cell types in the adult brain of some mammals. NPCs are capable of dividing and differentiating into a restricted repertoire of neuronal and glial cell types. In this study, the proliferation of NPCs was evaluated in CD-1 adult male mice chronically infected with the T. gondii ME49 strain. Histological brain sections from the infected mice were evaluated in order to observe T. gondii tissue cysts. Sagittal and coronal sections from the subventricular zone of the lateral ventricles and from the subgranular zone of the hippocampal dentate gyrus, as well as sagittal sections from the rostral migratory stream, were obtained from infected and non-infected mice previously injected with bromodeoxyuridine (BrdU). A flotation immunofluorescence technique was used to identify BrdU+ NPC. The scanning of BrdU+ cells was conducted using a confocal microscope, and the counting was performed with ImageJ® software (version 1.48q). In all the evaluated zones from the infected mice, a significant proliferation of the NPCs was observed when compared with that of the control group. We concluded that chronic infection with T. gondii increased the proliferation of NPCs in the three evaluated zones. Regardless of the role these cells are playing, our results could be useful to better understand the pathogenesis of chronic toxoplasmosis.

Main Cardiac Histopathologic Alterations in the Acute Phase of Trypanosoma cruzi Infection in a Murine Model.

Symptoms in the acute phase of Chagas disease are usually mild and nonspecific. However, after several years, severe complications like dilated heart failure and even death may arise in the chronic phase. Due to the lack of specific symptoms in the acute phase, the aim of this work was to describe and analyze the cardiac histopathology during this phase in a CD1 mouse model by assessing parasitism, fibrotic damage, and the presence and composition of a cellular infiltrate, to determine its involvement in the pathogenesis of lesions in the cardiac tissue. Our results indicate that the acute phase lasts about 62 days post-infection (dpi). A significant increase in parasitemia was observed since 15 dpi, reaching a maximum at 33 dpi (4.1 × 106). The presence of amastigote nests was observed at 15-62 dpi, with a maximum count of 27 nests at 35 dpi. An infiltrate consisting primarily of macrophages and neutrophils was found in the cardiac tissue within the first 30 days, but the abundance of lymphocytes showed an 8 ≥ fold increase at 40-62 dpi. Unifocal interstitial fibrosis was identified after 9 dpi, which subsequently showed a 16 ≥ fold increase at 40-60 dpi, along with a 50% mortality rate in the model under study. The increased area of fibrotic lesions revealed progression in the extent of fibrosis, mainly at 50-62 dpi. The presence of perivasculitis and thrombus circulation disorders was seen in the last days (62 dpi); finally, cases of myocytolysis were observed at 50 and 62 dpi. These histopathological alterations, combined with collagen deposition, seem to lead to the development of interstitial fibrosis and damage to the cardiac tissue during the acute phase of infection. This study provides a more complete understanding of the patterns of histopathological abnormalities involved in the acute phase, which could help the development of new therapies to aid the preclinical tests of drugs for their application in Chagas disease.

Response to Infection by Trypanosoma cruzi in a Murine Model.

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 (r 2 = 0.930), while correlation between the presence of fibrosis and of amastigote nests was weak (r 2 = 0.306), and that between fibrosis and lymphocyte infiltration on 100 dpi was strong (r 2 = 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.

Trypanosoma cruzi: A review of biological and methodological factors in Mexican strains.

Trypanosoma cruzi, responsible for Chagas disease, is a serious public health problem in Latin America with eight million people infected in the world. Clinical manifestations observed in humans due to T. cruzi infection are largely associated with the wide biological and genetic heterogeneity of the parasite. This review presents an overview of the parasitological aspects of various strains of T. cruzi isolated mainly in Mexico, as well as an analysis of the methodological processes used to determine their virulence that could be influencing their biological characterization. We emphasize the importance of using uniform protocols to study T. cruzi virulence, taking into account factors related to: strain (i.e. developmental stage, lineage, biological origin, genetic variability), animal model used (i.e. role of hormones, host immune response, age) and methodology (i.e. inoculum size, inoculation route, and laboratory conditions used during strain maintenance). These uniform protocols will then allow proposing elements for understanding clinical evolution and management of the disease, for providing adequate treatment, and for developing tools for future vaccines against Chagas disease.

Th-17 cytokines are associated with severity of Trypanosoma cruzi chronic infection in pediatric patients from endemic areas of Mexico.

In Chagas disease the clinical, acute and chronic manifestations are the result of the interaction between the parasite and the host factors. The balance between inflammatory and anti-inflammatory immune responses is essential for the increase or resolution of the manifestations in individuals infected with T. cruzi. To identify if children with chronic Chagas disease and heart injury is related with non-regulated Th1, Th2 and Th17 responses. We included 31 children with T. cruzi confirmed chronic infection from endemic areas of Mexico. Subsequently, they were separated according to their ECHO and ECG results into three groups according to the severity of cardiac involvement. Circulating Th1, Th2 and Th17 cytokine profiles were performed by Luminex assays and the results were analyzed by bivariate and multivariable analysis. Patients were classified in asymptomatic chronic (group 1, N=12); individuals with IRBBB in ECG and incipient lesions in ECHO (Group 2, N=8) and Patients with severe chronic symptomatic disease (Group 3, N=11). The analysis of immune mediators revealed that patients with severe cardiac manifestations had significant higher levels (p <0.05) of Th17 related cytokines including IL-17 and IL-6 as well as IFN-γ and IL-2. Also patients with severe cardiomyopathy exhibit increased levels of IL-13 (p <0.05) after multivariate analysis. High levels of Th17 related cytokines including IL-17, IFN-γ, IL-6 and IL-2 and pro-fibrotic factors such as IL-13 could be associated to the severity of cardiac involvement in children with chronic T. cruzi infection. These cytokines could be useful as indicators for the early identification of cardiac damage associated to the T. cruzi infection.