Increased heart fibrosis and acute infection in a murine Chagas disease model associated with organophosphorus pesticide metabolite exposure

AbstractSome reports suggest that exposure to organophosphorus (OP) pesticides increases the incidence of infections. Ethylated dialkylphosphates (EtDAPs) are metabolites of OP pesticides widely distributed with immunomodulatory potential. Chagas disease is produced by Trypanosoma cruzi parasites, and resolution of this infection requires the activation of inflammatory macrophages (MΦ), which results in cardiac fibrosis. Some reports indicate that EtDAPs increase the amount of the anti-inflammatory alternatively activated MΦ (M2; CD206+F4/80+). Therefore, we analyzed the course of T. cruzi infection, MΦ profiles from peritoneal exudate cells (PECs), inflammatory cell infiltration and fibrosis in the heart of BALB/c mice exposed to diethyldithiophosphate (DEDTP), diethylthiophosphate (DETP) or diethylphosphate (DEP, 0.01 g/kg), common DAPs produced by OP pesticides, 24 h before infection with T. cruzi. We found that DEDTP increased the parasite burden in blood by 99% at the peak of the infection and enhanced the myocardial damage due to an increase in infiltrated inflammatory cells (induced by DEDTP or DETP) and fibrosis (induced by EtDAPs). In the PECs, exposure to EtDAPs increased the proportion of the MΦ subpopulations of M2a, M2b and M2d, which are associated with tissue repair. These results indicate that exposure to EtDAPs can exacerbate the acute phase of a parasitic infection and increase the long-term damage to the heart.

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3D mapping of host-parasite-microbiome interactions reveals metabolic determinants of tissue tropism and disease tolerance in Chagas disease

10.1101/727917 ◽

2019 ◽

Cited By ~ 3

Author(s):

Ekram Hossain ◽

Sharmily Khanam ◽

Chaoyi Wu ◽

Sharon Lostracco-Johnson ◽

Diane Thomas ◽

...

Keyword(s):

Chagas Disease ◽

Large Intestine ◽

Large Scale ◽

Scale Effects ◽

Parasitic Infection ◽

Parasite Burden ◽

Acute Stage ◽

Disease Tolerance ◽

Chronic Stage ◽

Spatially Resolved

AbstractChagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi protozoa. Over 8 million people worldwide are T. cruzi-positive, 20-30% of which will develop cardiomyopathy, megaoesophagus and/or megacolon. The mechanisms leading to gastrointestinal (GI) symptom development are however poorly understood. To address this issue, we systematically characterized the spatial impact of experimental T. cruzi infection on the microbiome and metabolome across the GI tract. The largest microbiota perturbations were observed in the proximal large intestine in both acute and chronic disease, with chronic-stage effects also observed in the cecum. Strikingly, metabolomic impact of acute-to-chronic stage transition differed depending on the organ, with persistent large-scale effects of infection primarily in the oesophagus and large intestine, providing a potential mechanism for GI pathology tropism in CD. Infection particularly affected acylcarnitine and lipid metabolism. Building on these observations, treatment of infected mice with carnitine-supplemented drinking water prevented acute-stage mortality with no changes in parasite burden. Overall, these results identified a new mechanism of disease tolerance in CD, with potential for the development of new therapeutic regimens. More broadly, these results highlight the potential of spatially-resolved metabolomic approaches to provide insight into disease pathogenesis, with translational applications for infectious disease drug development.

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Glutamine increases body weight and decreases myocardial damage in Trypanosoma cruzi-infected mice treated with nifurtimox.

Revista de Investigaciones Altoandinas - Journal of High Andean Research ◽

10.18271/ria.2021.210 ◽

2021 ◽

Vol 23 (1) ◽

pp. 10-16

Author(s):

Carmen Marín-Tello ◽

◽

César Sánchez-Marín ◽

Luis Arteaga-Temoche ◽

◽

...

Keyword(s):

Body Weight ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Rural Areas ◽

Cardiac Tissue ◽

Parasitic Infection ◽

Myocardial Damage ◽

Glutamine Supplementation ◽

Histopathological Analysis ◽

Standard Diet

Chagas disease, a parasitic infection caused by the protist Trypanosoma cruzi, affect the poorest populations, living in remote, rural areas and urban slums. Although this drug is effective against Chagas disease present a number of serious side effects. In residents of high Andean areas with megacolon it can lead to cardiomyopathies. The aim of this study was to investigate whether dietary supplementation with L-glutamine may alleviate some of these symptoms because of its previously observed anti-inflammatory properties. We studied two groups of T. cruzi-infected mice receiving treatment with nifurtimox. One group was fed the standard diet, while the other group’s diet was supplemented with Glutamine. We found that Glutamine supplementation increases body weight (p<0.001), decreases heart mass to body mass ratio (p<0.001), and decreases the number of amastigotes present in cardiac tissue. Additionally, histopathological analysis showed less heart tissue damage in the group that received Glutaminne in their diet. Therefore, our findings suggest that Glutamine supplementation improves nifurtimox treatment outcomes of T. cruzi infection.

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Acute Pediatric Chagas Disease in Antioquia, Colombia: A Geographic Location of Suspected Oral Transmission

Microorganisms ◽

10.3390/microorganisms10010008 ◽

2021 ◽

Vol 10 (1) ◽

pp. 8

Author(s):

Lídia Gual-Gonzalez ◽

Catalina Arango-Ferreira ◽

Laura Camila Lopera-Restrepo ◽

Omar Cantillo-Barraza ◽

Daniela Velásquez Marín ◽

...

Keyword(s):

Chagas Disease ◽

Parasitic Infection ◽

Clinical Manifestations ◽

Geographic Location ◽

Myocardial Damage ◽

Geographic Region ◽

Structural Barriers ◽

Oral Transmission ◽

Physician Awareness ◽

Epidemiologic Risk

Chagas disease, Trypanosoma cruzi infection, is an insidious cause of heart failure in Latin America. Early diagnosis and treatment are critical to prevent irreversible myocardial damage that progressively accumulates over decades. Several structural barriers account for the less than 1% of cases in Colombia being treated, including poor physician knowledge, especially considering that some regions are considered non-endemic. The two cases reported here represent an emerging epidemiologic scenario associated with pediatric Chagas disease. Both cases are suspected oral transmitted parasitic infection in a geographic region of Colombia (Andean region of Antioquia) where no previous oral transmission of Chagas disease had been reported. Their clinical histories and course of disease are presented here to increase physician awareness of the epidemiologic risk factors and clinical manifestations associated with pediatric oral Chagas disease in Antioquia department, Colombia.

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Recombinant Enolase of Trypanosoma cruzi as a Novel Vaccine Candidate against Chagas Disease in a Mouse Model of Acute Infection

Journal of Immunology Research ◽

10.1155/2018/8964085 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 7

Author(s):

Minerva Arce-Fonseca ◽

María Cristina González-Vázquez ◽

Olivia Rodríguez-Morales ◽

Verónica Graullera-Rivera ◽

Alberto Aranda-Fraustro ◽

...

Keyword(s):

Immune Response ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Acute Phase ◽

Acute Infection ◽

Parasite Burden ◽

Protozoan Parasite ◽

World Health ◽

Protective Effects ◽

Th2 Immune Response

Trypanosoma cruzi is the protozoan parasite that causes Chagas disease, which is considered by the World Health Organization to be a neglected tropical disease. Two drugs exist for the treatment of Chagas disease, nifurtimox and benznidazole; they are only effective in the acute phase, and a vaccine is currently not available. In this study, we used the recombinant enolase from T. cruzi H8 strain (MHOM/MX/1992/H8 Yucatán) (rTcENO) and its encoding DNA (pBKTcENO) to immunize mice and evaluate their protective effects in an experimental murine model of acute phase infection. Our results showed that mice vaccinated with rTcENO or its encoding DNA were able to generate typical specific antibodies (IgG1, IgG2a, and IgG2b), suggesting that a mixed Th1/Th2 immune response was induced. The parasite burden in the blood was reduced to 69.8% and 71% in mice vaccinated with rTcENO and pBKTcENO, respectively. The group vaccinated with rTcENO achieved 75% survival, in contrast to the group vaccinated with pBKTcENO that showed no survival in comparison to the control groups. Moreover, rTcENO immunization elevated the production of IFN-γ and IL-2 after the parasite challenge, suggesting that the Th1-type immune response was polarized. These results indicated that rTcENO could be used as a vaccine against Chagas disease.

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Physical Exercise Promotes a Reduction in Cardiac Fibrosis in the Chronic Indeterminate Form of Experimental Chagas Disease

Frontiers in Immunology ◽

10.3389/fimmu.2021.712034 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yasmin Pedra-Rezende ◽

Juliana M. C. Barbosa ◽

Ana Cristina S. Bombaça ◽

Luiza Dantas-Pereira ◽

Daniel Gibaldi ◽

...

Keyword(s):

Chagas Disease ◽

Oxidative Metabolism ◽

Cardiac Fibrosis ◽

Training Session ◽

Exercise Program ◽

Inflammatory Cells ◽

Physical Exercises ◽

Qt Intervals ◽

Limited Effectiveness ◽

Indeterminate Form

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected tropical disease and a health problem in Latin America. Etiological treatment has limited effectiveness in chronic CD; thus, new therapeutic strategies are required. The practice of physical exercises has been widely advocated to improve the quality of life of CD patients. The most frequent clinical CD manifestation is the chronic indeterminate form (CIF), and the effect of physical exercises on disease progression remains unknown. Here, in a CIF model, we aimed to evaluate the effect of physical exercises on cardiac histological, parasitological, mitochondrial, and oxidative metabolism, electro and echocardiographic profiles, and immunological features. To establish a CIF model, BALB/c and C57BL/6 mice were infected with 100 and 500 trypomastigotes of the Y T. cruzi strain. At 120 days postinfection (dpi), all mouse groups showed normal PR and corrected QT intervals and QRS complexes. Compared to BALB/c mice, C57BL/6 mice showed a lower parasitemia peak, mortality rate, and less intense myocarditis. Thus, C57BL/6 mice infected with 500 parasites were used for subsequent analyses. At 120 dpi, a decrease in cardiac mitochondrial oxygen consumption and an increase in reactive oxygen species (ROS) were detected. When we increased the number of analyzed mice, a reduced heart rate and slightly prolonged corrected QT intervals were detected, at 120 and 150 dpi, which were then normalized at 180 dpi, thus characterizing the CIF. Y-infected mice were subjected to an exercise program on a treadmill for 4 weeks (from 150 to 180 dpi), five times per week in a 30–60-min daily training session. At 180 dpi, no alterations were detected in cardiac mitochondrial and oxidative metabolism, which were not affected by physical exercises, although ROS production increased. At 120 and 180 dpi, comparing infected and non-infected mice, no differences were observed in the levels of plasma cytokines, indicating that a crucial biomarker of the systemic inflammatory profile was absent and not affected by exercise. Compared with sedentary mice, trained Y-infected mice showed similar parasite loads and inflammatory cells but reduced cardiac fibrosis. Therefore, our data show that physical exercises promote beneficial changes that may prevent CD progression.

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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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Major Kinds of Drug Targets in Chagas Disease or American Trypanosomiasis

Current Drug Targets ◽

10.2174/1389450120666190423160804 ◽

2019 ◽

Vol 20 (11) ◽

pp. 1203-1216 ◽

Cited By ~ 1

Author(s):

Vilma G. Duschak

Keyword(s):

Chagas Disease ◽

Latin American ◽

Drug Targets ◽

Defense Mechanisms ◽

Cysteine Proteinase ◽

Parasitic Infection ◽

Etiologic Agent ◽

World Health ◽

American Trypanosomiasis ◽

Group I

American Trypanosomiasis, a parasitic infection commonly named Chagas disease, affects millions of people all over Latin American countries. Presently, the World Health Organization (WHO) predicts that the number of international infected individuals extends to 7 to 8 million, assuming that more than 10,000 deaths occur annually. The transmission of the etiologic agent, Trypanosoma cruzi, through people migrating to non-endemic world nations makes it an emergent disease. The best promising targets for trypanocidal drugs may be classified into three main groups: Group I includes the main molecular targets that are considered among specific enzymes involved in the essential processes for parasite survival, principally Cruzipain, the major antigenic parasite cysteine proteinase. Group II involves biological pathways and their key specific enzymes, such as Sterol biosynthesis pathway, among others, specific antioxidant defense mechanisms, and bioenergetics ones. Group III includes the atypical organelles /structures present in the parasite relevant clinical forms, which are absent or considerably different from those present in mammals and biological processes related to them. These can be considered potential targets to develop drugs with extra effectiveness and fewer secondary effects than the currently used therapeutics. An improved distinction between the host and the parasite targets will help fight against this neglected disease.

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Current knowledge of Chagas-related heart disease among pediatric cardiologists in the United States

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-01924-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Sanchi Malhotra ◽

Imran Masood ◽

Noberto Giglio ◽

Jay D. Pruetz ◽

Pia S. Pannaraj

Keyword(s):

United States ◽

Differential Diagnosis ◽

Heart Disease ◽

Chagas Disease ◽

Latin American ◽

Current Knowledge ◽

Parasitic Infection ◽

The United States ◽

Cardiac Complications ◽

The U.S

Abstract Background Chagas disease is a pathogenic parasitic infection with approximately 8 million cases worldwide and greater than 300,000 cases in the United States (U.S.). Chagas disease can lead to chronic cardiomyopathy and cardiac complications, with variable cardiac presentations in pediatrics making it difficult to recognize. The purpose of our study is to better understand current knowledge and experience with Chagas related heart disease among pediatric cardiologists in the U.S. Methods We prospectively disseminated a 19-question survey to pediatric cardiologists via 3 pediatric cardiology listservs. The survey included questions about demographics, Chagas disease presentation and experience. Results Of 139 responses, 119 cardiologists treat pediatric patients in the U.S. and were included. Most providers (87%) had not seen a case of Chagas disease in their practice; however, 72% also had never tested for it. The majority of knowledge-based questions about Chagas disease cardiac presentations were answered incorrectly, and 85% of providers expressed discomfort with recognizing cardiac presentations in children. Most respondents selected that they would not include Chagas disease on their differential diagnosis for presentations such as conduction anomalies, myocarditis and/or apical aneurysms, but would be more likely to include it if found in a Latin American immigrant. Of respondents, 87% agreed that they would be likely to attend a Chagas disease-related lecture. Conclusions Pediatric cardiologists in the U.S. have seen very few cases of Chagas disease, albeit most have not sent testing or included it in their differential diagnosis. Most individuals agreed that education on Chagas disease would be worth-while.

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A double-edged sword of immuno-microenvironment in cardiac homeostasis and injury repair

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00455-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Kang Sun ◽

Yi-yuan Li ◽

Jin Jin

Keyword(s):

Nk Cells ◽

Cardiac Remodeling ◽

Cardiac Fibrosis ◽

Cardiac Tissue ◽

Early Stage ◽

Cardiac Injury ◽

Inflammatory Cells ◽

Treg Cells ◽

Scar Formation

AbstractThe response of immune cells in cardiac injury is divided into three continuous phases: inflammation, proliferation and maturation. The kinetics of the inflammatory and proliferation phases directly influence the tissue repair. In cardiac homeostasis, cardiac tissue resident macrophages (cTMs) phagocytose bacteria and apoptotic cells. Meanwhile, NK cells prevent the maturation and transport of inflammatory cells. After cardiac injury, cTMs phagocytose the dead cardiomyocytes (CMs), regulate the proliferation and angiogenesis of cardiac progenitor cells. NK cells prevent the cardiac fibrosis, and promote vascularization and angiogenesis. Type 1 macrophages trigger the cardioprotective responses and promote tissue fibrosis in the early stage. Reversely, type 2 macrophages promote cardiac remodeling and angiogenesis in the late stage. Circulating macrophages and neutrophils firstly lead to chronic inflammation by secreting proinflammatory cytokines, and then release anti-inflammatory cytokines and growth factors, which regulate cardiac remodeling. In this process, dendritic cells (DCs) mediate the regulation of monocyte and macrophage recruitment. Recruited eosinophils and Mast cells (MCs) release some mediators which contribute to coronary vasoconstriction, leukocyte recruitment, formation of new blood vessels, scar formation. In adaptive immunity, effector T cells, especially Th17 cells, lead to the pathogenesis of cardiac fibrosis, including the distal fibrosis and scar formation. CMs protectors, Treg cells, inhibit reduce the inflammatory response, then directly trigger the regeneration of local progenitor cell via IL-10. B cells reduce myocardial injury by preserving cardiac function during the resolution of inflammation.

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Upregulated Expression of Cytotoxicity-Related Genes in IFN-γKnockout Mice withSchistosoma japonicumInfection

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/864945 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Xiaotang Du ◽

Jingjiao Wu ◽

Meijuan Zhang ◽

Yanan Gao ◽

Donghui Zhang ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Schistosoma Japonicum ◽

Fas Ligand ◽

Acute Infection ◽

Acquired Resistance ◽

Parasite Burden ◽

Cytotoxic T Cell ◽

Igg Antibody

It is well accepted that IFN-γis important to the development of acquired resistance against murine schistosomiasis. However, thein vivorole of this immunoregulatory cytokine in helminth infection needs to be further investigated. In this study, parasite burden and host immune response were observed in IFN-γknockout mice (IFNg KO) infected withSchistosoma japonicumfor 6 weeks. The results suggested that deficiency in IFN-γled to decreased egg burden in mice, with low schistosome-specific IgG antibody response and enhanced activation of T cells during acute infection. Microarray and qRT-PCR data analyses showed significant upregulation of some cytotoxicity-related genes, including those from the granzyme family, tumor necrosis factor, Fas Ligand, and chemokines, in the spleen cells of IFNg KO mice. Furthermore, CD8+cells instead of NK cells of IFNg KO mice exhibited increased transcription of cytotoxic genes compared with WT mice. Additionally,Schistosoma japonicum-specific egg antigen immunization also could activate CD8+T cells to upregulate the expression of cytotoxic genes in IFNg KO mice. Our data suggest that IFN-γis not always a positive regulator of immune responses. In certain situations, the disruption of IFN-γsignaling may up-regulate the cytotoxic T-cell-mediated immune responses to the parasite.

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