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1.
Life Sci ; 257: 118067, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652140

RESUMO

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Diminazena/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Animais , Linhagem Celular , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Diminazena/administração & dosagem , Diminazena/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/tratamento farmacológico , Miocardite/parasitologia , Miócitos Cardíacos/parasitologia , Miosite/tratamento farmacológico , Miosite/parasitologia , Fragmentos de Peptídeos/metabolismo , Ratos , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacologia
2.
Int J Cardiovasc Imaging ; 36(11): 2209-2219, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32613382

RESUMO

Chagas' disease (CD), caused by the parasite Trypanosoma cruzi, is the leading cause of cardiac disability from infectious diseases in Central and South America. The disease progresses through an extended, asymptomatic form characterized by latency without clinical manifestations into a symptomatic form with cardiac and gastro-intestinal manifestations. In the terminal phase, chronic Chagas' myocarditis results in extensive myocardial fibrosis, chamber enlargement with aneurysms and ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) has proven useful in characterizing myocardial fibrosis (MF). Sub-epicardial and mid-wall fibrosis are less common patterns of MF in CHD than transmural scar, which resembles myocardial infarction. Commonly involved areas of MF include the left ventricular apex and basal infero-lateral wall, suggesting a role for watershed ischemia in the pathophysiology of MF. Electrophysiology studies have helped refine the relationship between MF and VT in this setting. This article reviews the patterns of MF in CHD and correlate these patterns with electrogram patterns to predict risk of ventricular arrhythmias and sudden death.


Assuntos
Potenciais de Ação , Cardiomiopatia Chagásica/diagnóstico por imagem , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Imagem por Ressonância Magnética , Miocárdio/patologia , Taquicardia Ventricular/diagnóstico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/fisiopatologia , Progressão da Doença , Fibrose , Sistema de Condução Cardíaco/parasitologia , Humanos , Valor Preditivo dos Testes , Taquicardia Ventricular/parasitologia , Taquicardia Ventricular/fisiopatologia
3.
PLoS Negl Trop Dis ; 14(5): e0007980, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433643

RESUMO

Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Animais , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteoma/genética , Proteoma/metabolismo , Proteômica , Transdução de Sinais , Trypanosoma cruzi/fisiologia
4.
Parasitol Res ; 119(6): 1829-1843, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32206887

RESUMO

The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2-RIDα/ß transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1-/-), and (3) a Swiss outbred mice. RID mice and non-transgenic mice (wild type, WT) were infected with blood trypomastigotes of Brazil strain. During the acute stage of infection, RID mice had lower parasitemia, lower heart inflammation, and a decrease in the relative distribution of parasite load from cardiac muscle tissue toward epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed among RID and WT at the chronic stage of infection. Aif1-/- and Aif1+/+ mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high-fat diet (HFD) or regular diet (RD). Interestingly, Aif1+/+ HFD infected mice showed the highest mortality. Swiss mice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα-, and IL-1ß-mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.


Assuntos
Cardiomiopatia Chagásica/patologia , Doença de Chagas/complicações , Dieta Hiperlipídica , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Feminino , Coração/parasitologia , Inflamação/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/patologia , Carga Parasitária , Trypanosoma cruzi/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
5.
J Immunol ; 204(6): 1571-1581, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060134

RESUMO

T cell-mediated immune response plays a crucial role in controlling Trypanosoma cruzi infection and parasite burden, but it is also involved in the clinical onset and progression of chronic Chagas' disease. Therefore, the study of T cells is central to the understanding of the immune response against the parasite and its implications for the infected organism. The complexity of the parasite-host interactions hampers the identification and characterization of T cell-activating epitopes. We approached this issue by combining in silico and in vitro methods to interrogate patients' T cells specificity. Fifty T. cruzi peptides predicted to bind a broad range of class I and II HLA molecules were selected for in vitro screening against PBMC samples from a cohort of chronic Chagas' disease patients, using IFN-γ secretion as a readout. Seven of these peptides were shown to activate this type of T cell response, and four out of these contain class I and II epitopes that, to our knowledge, are first described in this study. The remaining three contain sequences that had been previously demonstrated to induce CD8+ T cell response in Chagas' disease patients, or bind HLA-A*02:01, but are, in this study, demonstrated to engage CD4+ T cells. We also assessed the degree of differentiation of activated T cells and looked into the HLA variants that might restrict the recognition of these peptides in the context of human T. cruzi infection.


Assuntos
Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Cardiomiopatia Chagásica/imunologia , Epitopos de Linfócito T/imunologia , Trypanosoma cruzi/imunologia , Antígenos de Protozoários/metabolismo , Argentina , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Cardiomiopatia Chagásica/sangue , Cardiomiopatia Chagásica/parasitologia , Simulação por Computador , ELISPOT , Epitopos de Linfócito T/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunidade Celular , Memória Imunológica , Testes de Liberação de Interferon-gama , Ativação Linfocitária , Masculino , Trypanosoma cruzi/metabolismo
6.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165658, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904415

RESUMO

Chagas disease is currently endemic to 21 Latin-American countries and has also become a global concern because of globalization and mass migration of chronically infected individuals. Prophylactic and therapeutic vaccination might contribute to control the infection and the pathology, as complement of other strategies such as vector control and chemotherapy. Ideal prophylactic vaccine would produce sterilizing immunity; however, a reduction of the parasite burden would prevent progression from Trypanosoma cruzi infection to Chagas disease. A therapeutic vaccine for Chagas disease may improve or even replace the treatment with current drugs which have several side effects and require long term treatment that frequently leads to therapeutic withdrawal. Here, we will review some aspects about sub-unit vaccines, the rationale behind the selection of the immunogen, the role of adjuvants, the advantages and limitations of DNA-based vaccines and the idea of therapeutic vaccines. One of the main limitations to advance vaccine development against Chagas disease is the high number of variables that must be considered and the lack of uniform criteria among research laboratories. To make possible comparisons, much of this review will be focused on experiments that kept many variables constant including antigen mass/doses, type of eukaryotic plasmid, DNA-delivery system, mice strain and sex, lethal and sublethal model of infection, and similar immunogenicity and efficacy assessments.


Assuntos
Antígenos de Protozoários/imunologia , Cardiomiopatia Chagásica/prevenção & controle , Vacinas Protozoárias/imunologia , Projetos de Pesquisa , Trypanosoma cruzi/imunologia , Animais , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Modelos Animais de Doenças , Feminino , Humanos , Imunogenicidade da Vacina , Masculino , Camundongos , Vacinas Protozoárias/administração & dosagem , Fatores Sexuais , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
7.
Biomedica ; 39(Supl. 2): 32-43, 2019 08 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31529832

RESUMO

Introduction: Trypanosoma cruzi is the causal agent of the American trypanosomiasis, an endemic disease in México. The commensal rodents Mus musculus and Rattus rattus are reservoirs of this parasite, which invades cardiac fibers and develops parasite nests causing various lesions. Histopathological studies in naturally infected rodents are scarce. Objective: To describe the types and frequencies of microscopic lesions in cardiac tissue of M. musculus and R. rattus infected with T. cruzi captured in Mérida, México. Materials and methods: The rodents were captured in suburban environments of Mérida. Cardiac tissue was extracted and processed by the paraffin inclusion technique and hematoxylin and eosin stained. The observation was made with a conventional microscope and all the lesions, as well as their degree, were identified. Results: Eight tissue samples of M. musculus and seven of R. rattus were studied. Parasite nests were found in 7/15, specifically 3/8 in M. musculus and 4/7 in R. rattus. The inflammatory infiltrate was the most frequent lesion. Other lesions were: Degeneration of cardiac fibers (8/15), congestion of blood vessels (6/15), and necrosis (5/15). Discussion: The lesions we observed have been described in experimental animal models and in humans with American trypanosomiasis. The inflammatory infiltrate has been identified as the most significant lesion in humans and reservoirs in the chronic stage of the disease. Conclusion: The lesions we described are associated with T. cruzi infection, which confirms that the rodents studied are reservoirs of this parasite.


Assuntos
Cardiomiopatia Chagásica/veterinária , Doença de Chagas/epidemiologia , Reservatórios de Doenças/parasitologia , Coração/parasitologia , Camundongos/parasitologia , Ratos/parasitologia , Doenças dos Roedores/parasitologia , Trypanosoma cruzi/isolamento & purificação , Animais , Animais Selvagens/parasitologia , Cardiomiopatia Chagásica/epidemiologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença de Chagas/transmissão , Doenças Endêmicas/veterinária , Feminino , Masculino , México/epidemiologia , Doenças dos Roedores/epidemiologia , Saúde Suburbana
8.
PLoS Negl Trop Dis ; 13(7): e0007602, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31365537

RESUMO

TGF-ß involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-ß signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TßR1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-ß signaling pathway reduced TGF-ß/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-ß inhibitors.


Assuntos
Benzamidas/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Coração/efeitos dos fármacos , Pirazóis/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Tripanossomicidas/uso terapêutico , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença Crônica , Conexina 43/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Coração/parasitologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Trypanosoma cruzi/efeitos dos fármacos
9.
PLoS Negl Trop Dis ; 13(7): e0007597, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31356587

RESUMO

CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNγ producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where they may play their effector activities. Using a model of induction of resistance to highly susceptible A/Sn mice using an ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression was upregulated on CD8+ T-cells, which selectively migrated towards its ligands CXCL9 and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. cruzi infection in a way associated with hampered cytotoxic activity and increased proapoptotic markers on the H2KK-restricted TEWETGQI-specific CD8+ T-cells. Furthermore, CXCR3 receptor critically guided TEWETGQI-specific effector CD8+ T-cells to the infected heart tissue that express CXCL9 and CXCL10. Overall, our study pointed CXCR3 and its ligands as key molecules to drive T. cruzi-specific effector CD8+ T-cells into the infected heart tissue. The unveiling of the process driving cell migration and colonization of infected tissues by pathogen-specific effector T-cells is a crucial requirement to the development of vaccine strategies.


Assuntos
Vacinas contra Adenovirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Cardiomiopatia Chagásica/imunologia , Quimiotaxia de Leucócito , Miocárdio/metabolismo , Receptores CXCR3/metabolismo , Trypanosoma cruzi/imunologia , Animais , Apoptose , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/prevenção & controle , Feminino , Coração/parasitologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/imunologia , Receptores CCR2/metabolismo , Baço/imunologia , Regulação para Cima , Vacinas de DNA/imunologia
10.
Catheter Cardiovasc Interv ; 94(4): 644-650, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31334914

RESUMO

INTRODUCTION: Chagas disease is one of the most relevant endemic parasitic diseases in Latin America, affecting approximately 6 million people. Overt Chagas heart disease is an ominous condition, occurring in 20-30% of infected individuals, which has besides the persistent myocarditis a peculiar intracardiac ganglionic neuronal depletion and dysautonomy. This study aims to evaluate the safety and feasibility of renal denervation for patients with advanced symptomatic Chagas cardiomyopathy. METHODS: Open-label prospective pilot study that randomized patients with Chagas heart disease to either renal denervation or conservative treatment (2:1 ratio). The primary endpoint was the incidence of major adverse events at 9 months, defined as a composite of all-cause death, myocardial infarction, stroke, need for renal artery invasive treatment, or worsening renal function. RESULTS: A total of 17 patients were allocated for renal denervation (n = 11) or conservative treatment (n = 6). Included patients had severe symptomatic heart disease, with markedly depressed left ventricular function (average ejection fraction 26.7 ± 4.9%). For patients randomized to renal denervation, the procedure was performed successfully and uneventfully. After 9 months, the primary endpoint occurred in 36.4% of patients in the renal denervation group and 50.0% in the control arm (p = .6). After 9 months, clinical, laboratory, functional, echocardiographic, and quality of life parameters were similar between groups. CONCLUSIONS: This pilot study suggests that renal denervation is safe and feasible in patients with Chagas cardiomyopathy, warranting future studies to better evaluate the clinical efficacy of the interventional strategy in improving the prognosis of this high-risk population.


Assuntos
Denervação Autônoma , Ablação por Cateter , Cardiomiopatia Chagásica/cirurgia , Insuficiência Cardíaca/cirurgia , Rim/inervação , Idoso , Denervação Autônoma/efeitos adversos , Denervação Autônoma/mortalidade , Brasil , Ablação por Cateter/efeitos adversos , Ablação por Cateter/mortalidade , Cardiomiopatia Chagásica/mortalidade , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/fisiopatologia , Estudos de Viabilidade , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/parasitologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento
11.
PLoS One ; 14(6): e0218260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31199841

RESUMO

Chronic inflammation, as a consequence of the persistent infection with Trypanosoma cruzi, leads to continuous activation of the immune system in patients with chronic Chagas disease. We have previously shown that increased sera levels of soluble P-selectin are associated with the severity of the cardiomyopathy distinctive of chronic Chagas disease. In this study, we explored the expression of biomarkers of platelet and endothelial activation, tissue remodeling, and mediators of the coagulation cascade in patients at different clinical stages of chronic Chagas heart disease. The frequencies of activated platelets, measured by the expression of CD41a and CD62P were decreased in patients with chronic Chagas disease compared with those in uninfected subjects, with an inverse association with disease severity. Platelet activation in response to adenosine diphosphate was also decreased in T. cruzi-infected subjects. A major proportion of T. cruzi infected subjects showed increased serum levels of fibrinogen. Patients with severe cardiac dysfunction showed increased levels of endothelin-1 and normal values of procollagen I. In conclusion, chronic infection with T. cruzi induced hemostatic alterations, even in those patients who do not yet present cardiac symptoms.


Assuntos
Plaquetas/patologia , Doença de Chagas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Plaquetas/parasitologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença de Chagas/metabolismo , Doença de Chagas/parasitologia , Doença Crônica , Endotelina-1/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Selectina-P/metabolismo , Pró-Colágeno/metabolismo , Trypanosoma cruzi/patogenicidade , Adulto Jovem
12.
PLoS Negl Trop Dis ; 13(5): e0007413, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31145733

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas' cardiomyopathy in ~30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective TH1-mediated immune response, thereby slowing or halting the progression of chronic Chagas' cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection.


Assuntos
Anticorpos Antiprotozoários/imunologia , Cardiomiopatia Chagásica/imunologia , Vacinas Protozoárias/administração & dosagem , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/prevenção & controle , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Interferon gama/genética , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/patologia , Parasitemia/imunologia , Parasitemia/parasitologia , Parasitemia/patologia , Parasitemia/prevenção & controle , Vacinas Protozoárias/imunologia , Células Th1/imunologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Vacinação
13.
Infect Immun ; 87(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936158

RESUMO

In chronic Trypanosoma cruzi infection, the cause of Chagas disease, life-threatening inflammatory diseases develop over time in the heart, esophagus, and colon of some patients. C57BL/6 mice infected with the myotropic Colombiana strain of T. cruzi model many of the immunological and parasitological features of human infection but succumb to chronic paralyzing myositis and skeletal muscle vasculitis, not cardiomyopathy or gastrointestinal disease. Here we show that T cell depletion in the chronic phase of this model increased tissue parasitism to acute-phase levels and induced neutrophilic skeletal muscle inflammation. Conversely, after daily treatment with the trypanocide benznidazole for 8 weeks during the chronic phase, viable parasites were no longer detectable, myositis completely resolved, vasculitis was ∼80% reduced, fibrosis was reduced, and myofiber morphology normalized. After the drug was discontinued, parasitism rebounded, and immunopathology recurred. The parasite load was statistically strongly correlated with the severity of inflammation. Thus, both T cell immunity and trypanocidal pharmacotherapy suppress to very low levels, but do not cure, T. cruzi infection, which is necessary and possibly sufficient to induce crippling chronic skeletal muscle myositis and vasculitis in the model.


Assuntos
Cardiomiopatia Chagásica/parasitologia , Músculo Esquelético/parasitologia , Miosite/parasitologia , Trypanosoma cruzi/fisiologia , Vasculite/parasitologia , Animais , Cardiomiopatia Chagásica/imunologia , Modelos Animais de Doenças , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Miosite/imunologia , Linfócitos T/imunologia , Vasculite/imunologia
14.
Arq Bras Cardiol ; 112(3): 240-246, 2019 03.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30916205

RESUMO

BACKGROUND: In the past two decades, a new epidemiological profile of Chagas' disease (CD) has been registered in the Brazilian Amazon where oral transmission has been indicated as responsible for the increase of acute cases. In the Amazonas state, five outbreaks of acute CD have been registered since 2004. The cardiac manifestations in these cases may be characterized by diffuse myocarditis, with alteration in the electrocardiogram (ECG) and transthoracic echocardiogram (TTE). OBJECTIVE: To perform a cardiac evaluation in autochthonous patients in the acute phase and at least one year after submitted to treatment for acute CD and evaluate the demographic variables associated with the presence of cardiac alterations. METHODS: We evaluated patients diagnosed with acute CD through direct parasitological or serological (IgM) methods from 2007 to 2015. These patients were treated with benznidazole and underwent ECG and TTE before and after treatment. We assumed a confidence interval of 95% (CI 95%, p < 0.05) for all variables analyzed. RESULTS: We observed 63 cases of an acute CD in which oral transmission corresponded to 75%. Cardiac alterations were found in 33% of the cases, with a greater frequency of ventricular repolarization alteration (13%), followed by pericardial effusion (10%) and right bundle branch block and left anterior fascicular block (2%). The follow-up occurred in 48 patients with ECG and 25 with TTE for a mean period of 15.5 ± 4.1 months after treatment. Of these, 8% presented normalization of the cardiac alterations in ECG, 62.5% remained with the normal exams. All of the patients presented normal results in TTE in the post-treatment period. As for the demographic variables, isolated cases presented more cardiac alterations than outbreaks (p = 0.044) as well as cases from Central Amazonas mesoregion (p = 0.020). CONCLUSIONS: Although cardiac alterations have not been frequent in most of the studied population, a continuous evaluation of the clinical-epidemiological dynamics of the disease in the region is necessary in order to establish preventive measures.


Assuntos
Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Adolescente , Adulto , Brasil/epidemiologia , Cardiomiopatia Chagásica/diagnóstico por imagem , Doença de Chagas/complicações , Doença de Chagas/epidemiologia , Ecocardiografia , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Trypanosoma cruzi/isolamento & purificação , Adulto Jovem
16.
Arq. bras. cardiol ; 112(3): 240-246, Mar. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-989336

RESUMO

Abstract Background: In the past two decades, a new epidemiological profile of Chagas' disease (CD) has been registered in the Brazilian Amazon where oral transmission has been indicated as responsible for the increase of acute cases. In the Amazonas state, five outbreaks of acute CD have been registered since 2004. The cardiac manifestations in these cases may be characterized by diffuse myocarditis, with alteration in the electrocardiogram (ECG) and transthoracic echocardiogram (TTE). Objective: To perform a cardiac evaluation in autochthonous patients in the acute phase and at least one year after submitted to treatment for acute CD and evaluate the demographic variables associated with the presence of cardiac alterations. Methods: We evaluated patients diagnosed with acute CD through direct parasitological or serological (IgM) methods from 2007 to 2015. These patients were treated with benznidazole and underwent ECG and TTE before and after treatment. We assumed a confidence interval of 95% (CI 95%, p < 0.05) for all variables analyzed. Results: We observed 63 cases of an acute CD in which oral transmission corresponded to 75%. Cardiac alterations were found in 33% of the cases, with a greater frequency of ventricular repolarization alteration (13%), followed by pericardial effusion (10%) and right bundle branch block and left anterior fascicular block (2%). The follow-up occurred in 48 patients with ECG and 25 with TTE for a mean period of 15.5 ± 4.1 months after treatment. Of these, 8% presented normalization of the cardiac alterations in ECG, 62.5% remained with the normal exams. All of the patients presented normal results in TTE in the post-treatment period. As for the demographic variables, isolated cases presented more cardiac alterations than outbreaks (p = 0.044) as well as cases from Central Amazonas mesoregion (p = 0.020). Conclusions: Although cardiac alterations have not been frequent in most of the studied population, a continuous evaluation of the clinical-epidemiological dynamics of the disease in the region is necessary in order to establish preventive measures.


Resumo Fundamento: Nas últimas duas décadas, um novo perfil epidemiológico da Doença de Chagas (DC) foi registrado na Amazônia brasileira, onde a transmissão oral foi indicada como responsável pelo aumento dos casos agudos. No estado do Amazonas, foram registrados cinco surtos da doença desde 2004. As manifestações cardíacas nesses casos podem ser caracterizadas por miocardite difusa, com alteração nos resultados eletrocardiograma (ECG) e ecocardiografia transtorácica (ETT). Objetivo: avaliar parâmetros cardíacos em pacientes autóctones com DC na fase aguda e em um ano ou mais após tratamento, e avaliar as variáveis demográficas associadas com a presença de alterações cardíacas. Métodos: Avaliamos os pacientes diagnosticados com DC aguda por método direto parasitológico e exame sorológico (IgM) entre 2007 e 2015. Os pacientes foram tratados com benzonidazol e submetidos à ECG e ETT antes e após tratamento. Assumimos um intervalo de confiança de 95% (p < 0,05) para todas as variáveis analisadas. Resultados: Observamos 63 casos de DC aguda em que a transmissão oral ocorreu em 75% dos casos. Alterações cardíacas foram encontradas em 33% dos casos, com maior frequência de repolarização ventricular (13%), seguida de derrame pericárdico (10%), e bloqueio do ramo direito e bloqueio fascicular anterior esquerdo (2%). O acompanhamento foi realizado com 48 pacientes com ECG e 25 com ETT por um período médio de 15,5±4,1 meses após o tratamento. Desses pacientes, observou-se normalização das alterações eletrocardiográficas em 8% dos pacientes, e 62,5% continuaram com os parâmetros normais. Todos os pacientes apresentaram resultados da ETT normais no período pós-tratamento. Quanto às variáveis demográficas, os casos isolados apresentaram mais alterações cardíacas em comparação aos casos de surtos (p=0,044) e os casos identificados na mesorregião do Amazonas Central (p = 0,020). Conclusões: Apesar de as alterações cardíacas não terem sido frequentes na maioria da população do estudo, é necessária uma avaliação contínua da dinâmica clínica-epidemiológica da doença na região para se estabelecer medidas preventivas.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Adulto Jovem , Tripanossomicidas/uso terapêutico , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Trypanosoma cruzi/isolamento & purificação , Brasil/epidemiologia , Ecocardiografia , Cardiomiopatia Chagásica/diagnóstico por imagem , Seguimentos , Doença de Chagas/complicações , Doença de Chagas/epidemiologia , Eletrocardiografia
17.
Curr Cardiol Rep ; 21(2): 8, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30747287

RESUMO

PURPOSE OF REVIEW: Chagas cardiomyopathy is a major public health disease in Latin America and, due to migration, is becoming a worldwide health and economic burden. This review sought to present the clinical and epidemiological aspects of Chagas cardiomyopathy, as well as some specific features and principles of treatment. We also retrospectively assessed our institutional experience with mechanical circulatory support in refractory heart failure due to Chagas cardiomyopathy over a 10-year period. RECENT FINDINGS: The role of antiparasitic treatment in patients with heart failure due to Chagas cardiomyopathy is controversial. Heart transplantation, although formerly contraindicated, is currently established as an important therapeutic option. Also, the favorable characteristics of Chagas patients, such as younger age, little comorbidity, and no reoperations or severe pulmonary hypertension, could be an advantage for a mechanical circulatory support indication in advanced heart failure due to Chagas cardiomyopathy. Despite the absence of large evidence-based data, much has been accomplished since Carlos Chagas' discovery one century ago. Our institutional experience shows that mechanical circulatory support in Chagas patients is associated with more successful bridging to heart transplantation when compared to non-Chagas patients.


Assuntos
Cardiomiopatia Chagásica/cirurgia , Doença de Chagas/complicações , Insuficiência Cardíaca/parasitologia , Transplante de Coração , Cardiomiopatia Chagásica/etiologia , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Insuficiência Cardíaca/cirurgia , Humanos , América Latina , Estudos Retrospectivos , Trypanosoma cruzi
18.
Acta Trop ; 189: 30-38, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30290285

RESUMO

It is still unclear whether the progression of acute to chronic Chagas cardiomyopathy is predominantly associated with the limited efficacy of aetiological chemotherapy, or with the pharmacological resistance profiles and pathogenicity of specific Trypanosoma cruzi strains. Thus, we tested the hypothesis that parasitic load could be a limited target of aetiological chemotherapy to prevent chronic cardiomyopathy in dogs infected by different T. cruzi strains. Animals were infected with benznidazole-susceptible (Berenice-78) and -resistant (VL-10 and AAS) strains of T. cruzi. A quantitative real-time PCR strategy was developed to comparatively quantify the parasite load of the three different strains using a single standard curve. For dogs infected with the VL-10 strain, benznidazole treatment reduced cardiac parasitism during the acute phase of infection. However, similar parasite load and collagen deposition were detected in the myocardium of treated and untreated animals in the chronic phase of the infection. In animals infected with the AAS strain, benznidazole reduced parasite load, myocarditis and type III collagen deposition in the acute phase. However, increased type III collagen deposition was verified in the chronic phase. Dogs infected with the Berenice-78 strain showed a parasitological cure and no evidence of myocardial fibrosis. Parasitic load and cardiac fibrosis presented no correlation in acute or chronic phases of T. cruzi infection. Our findings in a canine model of Chagas disease suggest that parasite burden is a limited predictor for disease progression after treatment and show that benznidazole, although not inducing parasitological cure, is able to prevent total fibrosis in the early stages of infection, as well as complete prevention of cardiac damage when it eliminates parasites at the onset of infection.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/prevenção & controle , Miocárdio/patologia , Carga Parasitária , Parasitemia/tratamento farmacológico , Trypanosoma cruzi , Doença Aguda , Animais , Cardiomiopatia Chagásica/parasitologia , Doença Crônica , Colágeno Tipo III/metabolismo , DNA de Protozoário/sangue , Modelos Animais de Doenças , Progressão da Doença , Cães , Resistência a Medicamentos , Fibrose , Coração/parasitologia , Miocárdio/metabolismo , Nitroimidazóis/uso terapêutico , Parasitemia/sangue , Parasitemia/parasitologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/genética
19.
Cytokine ; 113: 285-290, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30037707

RESUMO

This study investigated the efficacy of the vaccine in liver of mice infected with the Trypanosoma cruzi (T. cruzi) and immunized with AdASP-2. For this purpose, histopathological analysis and gene expression of COX-2, TNF-alpha, TNFR, iNOS, cytochrome C, caspase-3, TLR4, IL-6 and IL10 were evaluated. The following groups were used in this study: Group 1 - Control Group (CTRL) animals received AdßGal vehicle; Group 2 - Infected Group (TC) animals were infected with T. cruzi; Group 3 - Immunized Group (AdASP-2): animals were immunized by AdASP-2 vaccine; Group 4 - Immunized and Infected Group (AdASP-2+TC) animals were infected with T. cruzi and immunized by AdSP-2 vaccine. A significant decrease of amastigote nests was noticed in the group of animals that were immunized with AdASP-2 and infected on the same day. COX-2 and TNF-alpha gene expressions increased in TC group, whereas TNF-alpha decreased in the TC+AdASP-2 group. TNFR expression was high in AdASP-2+TC group. iNOS expression was high for all experimental groups whereas cytochrome C decreased for all experimental groups. Caspase 3 increased in TC and TC+AdASP-2 groups. The gene expression of TLR4 and IL-10 showed an increase in AdASP-2+TC group. Finally, hepatic fibrosis was noticed to TC and AdASP-2 + TC groups. Taken together, our results demonstrated that vaccination with AdASP-2 was effective against the acute phase of experimental Chagas disease as a result of a more powerful and rapid immune response closely related to expression of some inflammatory genes, such as iNOS, TNF-alpha, TLR 4, and IL-10.


Assuntos
Cardiomiopatia Chagásica/imunologia , Cirrose Hepática/imunologia , Fígado/imunologia , Neuraminidase/imunologia , Vacinas Protozoárias/imunologia , Trypanosoma cruzi/imunologia , Adenoviridae , Animais , Caspase 3/imunologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/prevenção & controle , Ciclo-Oxigenase 2/imunologia , Citocromos c/imunologia , Citocinas/imunologia , Feminino , Fígado/parasitologia , Fígado/patologia , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Camundongos , Óxido Nítrico Sintase Tipo II/imunologia , Receptor 4 Toll-Like/imunologia
20.
Free Radic Biol Med ; 130: 23-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30359758

RESUMO

BACKGROUND: Chagas cardiomyopathy, caused by Trypanosoma cruzi infection, continues to be a neglected illness, and has a major impact on global health. The parasite undergoes several stages of morphological and biochemical changes during its life cycle, and utilizes an elaborated antioxidant network to overcome the oxidants barrier and establish infection in vector and mammalian hosts. Trypanothione synthetase (TryS) catalyzes the biosynthesis of glutathione-spermidine adduct trypanothione (T(SH)2) that is the principal intracellular thiol-redox metabolite in trypanosomatids. METHODS AND RESULTS: We utilized genetic overexpression (TryShi) and pharmacological inhibition approaches to examine the role of TryS in T. cruzi proliferation, tolerance to oxidative stress and resistance to anti-protozoal drugs. Our data showed the expression and activity of TryS was increased in all morphological stages of TryShi (vs. control) parasites. In comparison to controls, the TryShi epimastigotes (insect stage) recorded shorter doubling time, and both epimastigotes and infective trypomastigotes of TryShi exhibited 36-71% higher resistance to H2O2 (50-1000 µM) and heavy metal (1-500 µM) toxicity. Treatment with TryS inhibitors (5-30 µM) abolished the proliferation and survival advantages against H2O2 pressure in a dose-dependent manner in both TryShi and control parasites. Further, epimastigote and trypomastigote forms of TryShi (vs. control) T. cruzi tolerated higher doses of benznidazole and nifurtimox, the drugs currently administered for acute Chagas disease treatment. CONCLUSIONS: TryS is essential for proliferation and survival of T. cruzi under normal and oxidant stress conditions, and provides an advantage to the parasite to develop resistance against currently used anti-trypanosomal drugs. TryS indispensability has been chemically validated with inhibitors that may be useful for drug combination therapy against Chagas disease.


Assuntos
Amida Sintases/metabolismo , Antioxidantes/metabolismo , Cardiomiopatia Chagásica/parasitologia , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/fisiologia , Amida Sintases/genética , Animais , Antiprotozoários/uso terapêutico , Proliferação de Células , Células Cultivadas , Cardiomiopatia Chagásica/tratamento farmacológico , Resistência a Medicamentos , Humanos , Oxirredução , Estresse Oxidativo , Proteínas de Protozoários/genética , Transgenes/genética
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