Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

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Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation through N-formyl peptide receptor 2 in a chronic murine model of Chagas disease

10.1101/2021.08.17.456695 ◽

2021 ◽

Author(s):

Ileana Carrillo ◽

Rayane Rabelo ◽

Cesar Barbosa ◽

Mariana Rates ◽

Sebasti&aacuten Fuentes-Retamal ◽

...

Keyword(s):

Inflammatory Response ◽

Chagas Disease ◽

Cardiac Tissue ◽

Chronic Phase ◽

Parasite Load ◽

Formyl Peptide Receptor ◽

Resolvin D1 ◽

Peptide Receptor ◽

Formyl Peptide ◽

Cruzi Infection

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. After years of infection and in the absence of treatment, the disease progresses from an acute and asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapy aid to regulate the pro-inflammatory state during the chronic phase of Chagas disease. C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in the immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. Thus, AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

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Early Immune Response Elicited by Different Trypanosoma cruzi Infective Stages

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.768566 ◽

2021 ◽

Vol 11 ◽

Author(s):

Brenda Celeste Gutierrez ◽

Estela Lammel ◽

Stella Maris González-Cappa ◽

Carolina Verónica Poncini

Keyword(s):

Immune Response ◽

Trypanosoma Cruzi ◽

Cardiac Tissue ◽

Acute Infection ◽

Lethal Dose ◽

Protozoan Parasite ◽

Parasite Load ◽

Different Populations ◽

Antigen Presenting

Trypanosoma cruzi is a protozoan parasite that affects millions of people in Latin America. Infection occurs by vectorial transmission or by transfusion or transplacental route. Immune events occurring immediately after the parasite entrance are poorly explored. Dendritic cells (DCs) are target for the parasite immune evasion mechanisms. Recently, we have demonstrated that two different populations of DCs display variable activation after interaction with the two infective forms of the parasite: metacyclic or blood trypomastigotes (mTp or bTp) in vitro. The skin constitutes a complex network with several populations of antigen-presenting cells. Previously, we have demonstrated T. cruzi conditioning the repertoire of cells recruited into the site of infection. In the present work, we observed that mTp and bTp inoculation displayed differences in cell recruitment to the site of infection and in the activation status of APCs in draining lymph nodes and spleen during acute infection. Animals inoculated with mTp exhibited 100% of survival with no detectable parasitemia, in contrast with those injected with bTp that displayed high mortality and high parasite load. Animals infected with mTp and challenged with a lethal dose of bTp 15 days after primary infection showed no mortality and incremented DC activation in secondary lymphoid organs compared with controls injected only with bTp or non-infected mice. These animals also displayed a smaller number of amastigote nests in cardiac tissue and more CD8 T cells than mice infected with bTp. All the results suggest that both Tp infective stages induce an unequal immune response since the beginning of the infection.

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The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

Pathogens ◽

10.3390/pathogens10091074 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1074

Author(s):

Natalia Vacani-Martins ◽

Marcelo Meuser-Batista ◽

Carina de Lima Pereira dos Santos ◽

Alejandro Marcel Hasslocher-Moreno ◽

Andrea Henriques-Pons

Keyword(s):

Immune Response ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Clinical Signs ◽

Cell Types ◽

Experimental Models ◽

Chronic Patients ◽

The Usa ◽

Multiple Cell ◽

Underlying Mechanisms

Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver’s participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.

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A Parasite Biomarker Set for Evaluating Benznidazole Treatment Efficacy in Patients with Chronic Asymptomatic Trypanosoma cruzi Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02436-18 ◽

2019 ◽

Vol 63 (10) ◽

Cited By ~ 4

Author(s):

Adriana Egui ◽

M. Carmen Thomas ◽

Ana Fernández-Villegas ◽

Elena Pérez-Antón ◽

Inmaculada Gómez ◽

...

Keyword(s):

T Cells ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Parasite Load ◽

Drastic Reduction ◽

Content Type ◽

Short Period ◽

Before And After ◽

Cruzi Infection

ABSTRACT One of the current greatest challenges of Chagas disease is the establishment of biomarkers to assess the efficacy of drugs in a short period of time. In this context, the reactivity of sera from 66 adults with chronic indeterminate Chagas disease (IND) for a set of four Trypanosoma cruzi antigens (KMP11, PFR2, HSP70, and 3973d) was analyzed before and after benznidazole treatment. The results showed that the reactivity against these antigens decreased at 9, 24, and 48 months after treatment. Moreover, the 42.4% and 68.75% of IND patients met the established standard criteria of therapeutic efficacy (STEC) at 24 and 48 months posttreatment, respectively. Meeting the STEC implied that there was a continuous decrease in the reactivity of the patient sera against the four antigens after treatment and that there was a substantial decrease in the reactivity for at least two of the antigens. This important decrease in reactivity may be associated with a drastic reduction in the parasite load, but it is not necessarily associated with a parasitological cure. After treatment, a positive PCR result was only obtained in patients who did not meet the STEC. The percentage of granzyme B+/perforin+ CD8+ T cells was significantly higher in patients who met the STEC than in those who did not meet the STEC (35.2% versus 2.2%; P < 0.05). Furthermore, the patients who met the STEC exhibited an increased quality of the multifunctional response of the antigen-specific CD8+ T cells compared with that in the patients who did not meet the STEC.

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Effects of betamethasone on the course of experimentai. Infection with Trypanosoma cruzi

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86821986000300006 ◽

1986 ◽

Vol 19 (3) ◽

pp. 161-164 ◽

Cited By ~ 5

Author(s):

Frederico G.C. Abath ◽

Yara M. Gomes ◽

Eridan M. Coutinho ◽

Silvia M.L. Montenegro ◽

Maria E.B. Melo ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Acute Phase ◽

Bacterial Infections ◽

Acute Infection ◽

Chronic Phase ◽

Control Group ◽

Cumulative Mortality ◽

Histopathological Findings ◽

Experimental Group

In this experiment, the effect of betamethasone administered in the early post- acute infection of mice by Trypanosoma cruzi was studied. This drug was administered during 30 days after the 42nd day of infection in a dose of 0.15 mg/day. The betamethasone treatment did not cause fresh outbreaks of parasitemia and the histopathological findings in the chronic phase were not different from those in the control group. The higher cumulative mortality after treatment in the experimental group was due to superimposed bacterial infections. Outbred albino mice infected with low numbers ofY strain Trypanosoma cruzi trypomastigotes were not suitable models for Chagas' disease, since after 7 months of observation only mild histological lesions developed in all the animais. Prolonged betamethasone treatment of mice infected with low numbers o/Trypanosoma cruzi of the Y strain, during the post-acute phase did not aggravate the course of infection.

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The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4993452 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Edio Maldonado ◽

Diego A. Rojas ◽

Fabiola Urbina ◽

Aldo Solari

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Heart Failure ◽

Immune Response ◽

Chronic Inflammation ◽

Chagas Disease ◽

Genetic Factors ◽

Cardiac Tissue ◽

Chronic Phase

Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosoma cruzi that affects several million people mainly in Latin American countries. Chagas disease has two phases, which are acute and chronic, both separated by an indeterminate time period in which the infected individual is relatively asymptomatic. The acute phase extends for 40-60 days with atypical and mild symptoms; however, about 30% of the infected patients will develop a symptomatic chronic phase, which is characterized by either cardiac, digestive, neurological, or endocrine problems. Cardiomyopathy is the most important and severe result of Chagas disease, which leads to left ventricular systolic dysfunction, heart failure, and sudden cardiac death. Most deaths are due to heart failure (70%) and sudden death (30%) resulting from cardiomyopathy. During the chronic phase, T. cruzi-infected macrophages respond with the production of proinflammatory cytokines and production of superoxide and nitric oxide by the NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) enzymes, respectively. During the chronic phase, myocardial changes are produced as a result of chronic inflammation, oxidative stress, fibrosis, and cell death. The cellular inflammatory response is mainly the result of activation of the NF-κB-dependent pathway, which activates gene expression of inflammatory cytokines, leading to progressive tissue damage. The persisting production of reactive oxygen species (ROS) is the result of mitochondrial dysfunction in the cardiomyocytes. In this review, we will discuss inflammation and oxidative damage which is produced in the heart during the chronic phase of Chagas disease and recent evidence on the role of macrophages and the production of proinflammatory cytokines during the acute phase and the origin of macrophages/monocytes during the chronic phase of Chagas disease. We will also discuss the contributing factors and mechanisms leading to the chronic inflammation of the cardiac tissue during the chronic phase of the disease as well as the innate and adaptive host immune response. The contribution of genetic factors to the progression of the chronic inflammatory cardiomyopathy of chronic Chagas disease is also discussed. The secreted extracellular vesicles (exosomes) produced for both T. cruzi and infected host cells can play key roles in the host immune response, and those roles are described. Lastly, we describe potential treatments to attenuate the chronic inflammation of the cardiac tissue, designed to improve heart function in chagasic patients.

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The Blockade of Interleukin-2 During the Acute Phase of Trypanosoma cruzi Infection Reveals Its Dominant Regulatory Role

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.758273 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jorge Nihei ◽

Fabiola Cardillo ◽

Jose Mengel

Keyword(s):

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Trypanosoma Cruzi ◽

Immune Responses ◽

Chagas Disease ◽

Acute Phase ◽

Acute Infection ◽

Dependent Manner ◽

Tissue Specific

Trypanosoma cruzi infection causes Chagas’ disease in humans. The infection activates the innate and adaptative immunity in an orchestrated immune response to control parasite growth, guaranteeing host survival. Despite an effective immune response to the parasite in the acute phase, the infection progresses to a chronic stage. The parasite infects different tissues such as peripheral neurons, the brain, skeletal muscle, and heart muscle, among many others. It is evident now that tissue-specific immune responses may develop along with anti-parasite immunity. Therefore, mechanisms to regulate immunity and to ensure tissue-specific tolerance are operating during the infection. Studying those immunoregulatory mechanisms is fundamental to improve host protection or control inflammatory reactions that may lead to pathology. The role of IL-2 during T. cruzi infection is not established. IL-2 production by T cells is strongly down-modulated early in the disease by unknown mechanisms and remains low during the chronic phase of the disease. IL-2 activates NK cells, CD4, and CD8 T cells and may be necessary to immunity development. Also, the expansion and maintenance of regulatory T cells require IL-2. Thus, IL-2 may be a key cytokine involved in promoting or down-regulating immune responses, probably in a dose-dependent manner. This study blocked IL-2 during the acute T. cruzi infection by using a neutralizing monoclonal antibody. The results show that parasitemia and mortality rate was lower in animals treated with anti-IL-2. The percentages and total numbers of CD4+CD25+Foxp3+ T cells diminished within three weeks of infection. The numbers of splenic activated/memory CD4 and CD8 splenic T cells increased during the acute infection. T cells producing IFN-γ, TNF-α and IL-10 also augmented in anti-IL-2-treated infected mice. The IL-2 blockade also increased the numbers of inflammatory cells in the heart and skeletal muscles and the amount of IL-17 produced by heart T cells. These results suggest that IL-2 might be involved in the immune regulatory response during the acute T. cruzi infection, dampening T cell activation through the expansion/maintenance of regulatory T cells and regulating IL-17 production. Therefore, the IL-2 pathway is an attractive target for therapeutic purposes in acute and chronic phases of Chagas’ disease.

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Disagreement between PCR and serological diagnosis of Trypanosoma cruzi infection in blood donors from a Colombian endemic region

Biomédica ◽

10.7705/biomedica.5441 ◽

2021 ◽

Vol 41 (Supl. 1) ◽

pp. 47-59

Author(s):

Liliana Torcoroma García Sánchez ◽

Jhancy Rocío Aguilar Jiménez ◽

Marly Yojhana Bueno ◽

Erika Marcela Moreno Moreno ◽

Herminia Ramírez ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Blood Donors ◽

False Negative ◽

Chronic Phase ◽

Antibody Detection ◽

Low Grade ◽

Endemic Region ◽

Infected People ◽

Cruzi Infection

Introduction: Chagas’ disease is the leading cause of infectious myocarditis worldwide. This infection caused by Trypanosoma cruzi is usually life-long and asymptomatic; however, the third part of infected people can develop severe or even fatal cardiomyopathy. As the parasitemia in the chronic phase is both low-grade and intermittent, T. cruzi infection is principally detected by serology, although this method has sensitivity and specificity limitations.Objective: To determine the level of agreement between serologic and molecular tests in 658 voluntary blood donors from six provinces in the Colombian department of Santander.Materials and methods: We evaluated an array of diagnostic technologies by cross-section sampling performing a serological double diagnostic test for T. cruzi antibody detection (Chagas III ELISA™, BiosChile Group, and ARCHITECT Chagas CMIA™, Abbott), and DNA detection by polymerase chain reaction (PCR). We collected the demographic, clinical, and epidemiological information of participants. The sample size was calculated using Epidat™ and the statistical analysis was done with Stata 12.1™.Results: PCR was six times more sensitive in detecting T. cruzi infection than ELISA/CMIA with prevalence values of 1.8% (12/658) and 0.3% (2/658), respectively, and kappa=0.28 (95%CI: -0.03 - 0.59). In contrast, serology showed a sensitivity of 16.7% (95%CI: 2.09 - 48.4) and a specificity of 100% (95%CI: 99.4 - 100). All seropositive samples were found to be positive by PCR.Conclusions: The implementation of PCR as a complementary method for screening donors could reduce the probability of false negative and the consequent risk of transfusional-transmission of Chagas’ disease, especially in endemic regions.

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