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

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

Current Medicinal Chemistry ◽

10.2174/0929867325666181101111819 ◽

2019 ◽

Vol 26 (36) ◽

pp. 6519-6543 ◽

Cited By ~ 1

Author(s):

Adriana Egui ◽

Paola Lasso ◽

Elena Pérez-Antón ◽

M. Carmen Thomas ◽

Manuel Carlos López

Keyword(s):

Immune Response ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Cardiac Tissue ◽

Acute Infection ◽

Clinical Status ◽

Chronic Phase ◽

Parasite Load ◽

Chronic Patients ◽

Cruzi Infection

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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Hematological alterations during experimental canine infection by Trypanosoma cruzi

Revista Brasileira de Parasitologia Veterinária ◽

10.1590/s1984-29612012000200015 ◽

2012 ◽

Vol 21 (2) ◽

pp. 151-156 ◽

Cited By ~ 14

Author(s):

Paulo Marcos Matta Guedes ◽

Vanja Maria Veloso ◽

Tiago Wilson Patriarca Mineo ◽

Juliana Santiago-Silva ◽

Geovan Crepalde ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Experimental Model ◽

Chagas Disease ◽

Experimental Infection ◽

Clinical Signs ◽

Beagle Dogs ◽

Canine Infection ◽

Loss Of Appetite ◽

Experimental Canine ◽

Hematological Alterations

To confirm that Beagle dogs are a good experimental model for Chagas disease, we evaluated hematological alterations during the acute and chronic phases in Beagle dogs infected with the Y, Berenice-78 (Be-78) and ABC strains of Trypanosomacruzi, correlating clinical signs with the parasitemia curve. We demonstrate that the acute phase of infection was marked by lethargy and loss of appetite. Simultaneously, we observed anemia, leukocytosis and lymphocytosis. Also,we describe hematological alterations and clinical signs that were positively correlated with the parasitemia during the experimental infection with the three strains of T.cruzi, and demonstrate that experimental infection of Beagle is a trustworthy model for Chagas disease.

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Targeting the Gut Microbiota in Chagas Disease: What Do We Know so Far?

Frontiers in Microbiology ◽

10.3389/fmicb.2020.585857 ◽

2020 ◽

Vol 11 ◽

Author(s):

Eduardo Duarte-Silva ◽

Livia H. Morais ◽

Gerard Clarke ◽

Wilson Savino ◽

Christina Peixoto

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Current Data ◽

Review Article ◽

Microbiota Composition ◽

Comorbid Conditions ◽

Therapeutic Approaches ◽

Gut Microbiota Composition

Chagas disease (CD) is a tropical and still neglected disease caused by Trypanosoma cruzi that affects >8 million of people worldwide. Although limited, emerging data suggest that gut microbiota dysfunction may be a new mechanism underlying CD pathogenesis. T. cruzi infection leads to changes in the gut microbiota composition of vector insects, mice, and humans. Alterations in insect and mice microbiota due to T. cruzi have been associated with a decreased immune response against the parasite, influencing the establishment and progression of infection. Further, changes in the gut microbiota are linked with inflammatory and neuropsychiatric disorders, comorbid conditions in CD. Therefore, this review article critically analyses the current data on CD and the gut microbiota of insects, mice, and humans and discusses its importance for CD pathogenesis. An enhanced understanding of host microbiota will be critical for the development of alternative therapeutic approaches to target CD, such as gut microbiota-directed interventions.

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Humoral Immune Response against P2β from Trypanosoma cruzi in Persons with Chronic Chagas Disease: Its Relationship with Treatment Against Parasites and Myocardial Damage

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2011.10-0261 ◽

2011 ◽

Vol 84 (4) ◽

pp. 575-580 ◽

Cited By ~ 11

Author(s):

Diana L. Fabbro ◽

Mirtha Streiger ◽

Mónica del Barco ◽

Verónica Olivera ◽

Susana Denner ◽

...

Keyword(s):

Immune Response ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Humoral Immune Response ◽

Myocardial Damage ◽

Humoral Immune ◽

Chronic Chagas Disease

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Experimental models in Chagas disease: a review of the methodologies applied for screening compounds against Trypanosoma cruzi

Parasitology Research ◽

10.1007/s00436-018-6084-3 ◽

2018 ◽

Vol 117 (11) ◽

pp. 3367-3380 ◽

Cited By ~ 7

Author(s):

Cristina Fonseca-Berzal ◽

Vicente J. Arán ◽

José A. Escario ◽

Alicia Gómez-Barrio

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Experimental Models

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Characterization of human infection by Leishmania spp. in the Northwest of Argentina: immune response, double infection with Trypanosoma cruzi and species of Leishmania involved

Parasitology ◽

10.1017/s0031182002002585 ◽

2003 ◽

Vol 126 (1) ◽

pp. 31-39 ◽

Cited By ~ 48

Author(s):

F. M. FRANK ◽

M. M. FERNÁNDEZ ◽

N. J. TARANTO ◽

S. P. CAJAL ◽

R. A. MARGNI ◽

...

Keyword(s):

Immune Response ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Human Infection ◽

Double Infection ◽

Strong Immune Response ◽

American Tegumentary Leishmaniasis ◽

Leishmania Spp ◽

Very High

The aims of this study were to characterize human American tegumentary leishmaniasis, which includes cutaneous, mucocutaneous and mucosal leishmaniasis, in Northwest Argentina, to determine the prevalence of double infection with Trypanosoma cruzi and to identify the species of Leishmania in this area. Most of the 330 leishmaniasis patients presented cutaneous ulcers (96·1%), 2·4% mucocutaneous and 1·5% the mucosal form (‘espundia’). The aetiological agents, determined by isoenzyme electrophoresis, were identified as Leishmania (Viannia) braziliensis in 16 out of 20 isolates and in the remaining 4 as Leishmania (Leishmania) amazonensis, the first ever-documented in Argentina. Sera analysed by ELISA and IFA using complex antigen from both T. cruzi and L. braziliensis showed a very high percentage of positives (66·3–78·2%). When antigens for specific diagnosis of Chagas' disease were used, 40·9% of the leishmaniasis patients were also found to be infected by T. cruzi. These results indicate that the strong immune response against T. cruzi gave no protection to Leishmania, in spite of the serological cross-reaction between these parasites. In addition, we showed that more than 40% of the patients would be misdiagnosed as chagasic if complex antigens, as epimastigotes or soluble fraction from epimastigotes, were used in IFA or ELISA. This is of paramount importance not only because patients' treatment would be associated to misdiagnosis but the fact that in many countries in Central and South America, a positive test for Chagas' disease means a rejection for those seeking employment.

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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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Advanced glycation end-products regulate extracellular matrix-adipocyte metabolic crosstalk in diabetes

Scientific Reports ◽

10.1038/s41598-019-56242-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Clarissa Strieder-Barboza ◽

Nicki A. Baker ◽

Carmen G. Flesher ◽

Monita Karmakar ◽

Christopher K. Neeley ◽

...

Keyword(s):

Extracellular Matrix ◽

Adipose Tissue ◽

Glucose Uptake ◽

Rho Gtpases ◽

Cell Types ◽

Scavenger Receptors ◽

Advanced Glycation ◽

Human Diabetes ◽

Multiple Cell ◽

Underlying Mechanisms

AbstractThe adipose tissue extracellular matrix (ECM) regulates adipocyte cellular metabolism and is altered in obesity and type 2 diabetes, but mechanisms underlying ECM-adipocyte metabolic crosstalk are poorly defined. Advanced glycation end-product (AGE) formation is increased in diabetes. AGE alter tissue function via direct effects on ECM and by binding scavenger receptors on multiple cell types and signaling through Rho GTPases. Our goal was to determine the role and underlying mechanisms of AGE in regulating human ECM-adipocyte metabolic crosstalk. Visceral adipocytes from diabetic and non-diabetic humans with obesity were studied in 2D and 3D-ECM culture systems. AGE is increased in adipose tissue from diabetic compared to non-diabetic subjects. Glycated collagen 1 and AGE-modified ECM regulate adipocyte glucose uptake and expression of AGE scavenger receptors and Rho signaling mediators, including the DIAPH1 gene, which encodes the human Diaphanous 1 protein (hDia1). Notably, inhibition of hDia1, but not scavenger receptors RAGE or CD36, attenuated AGE-ECM inhibition of adipocyte glucose uptake. These data demonstrate that AGE-modification of ECM contributes to adipocyte insulin resistance in human diabetes, and implicate hDia1 as a potential mediator of AGE-ECM-adipocyte metabolic crosstalk.

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