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1.
Medicine (Baltimore) ; 99(51): e23773, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371145

RESUMO

ABSTRACT: Chagas disease affects approximately 7 million people, causing disability and mortality in the most productive life stages of infected individuals. Considering the lifestyle of the world population, metabolic syndrome is a synergistic factor for an increased cardiovascular risk of patients with Chagas disease.This study transversally evaluated the metabolic and immunological profiles of patients with indeterminate (IF) and cardiac (CF) forms of Chagas disease and their correlations with left ventricular dysfunction (LVD).Clinical and electrical bioimpedance analysis, levels of cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-17, IL-10, and IL-33) and adipocytokines (adiponectin, leptin, and resistin), metabolic syndrome components, and brain natriuretic peptide (BNP) levels were assessed in 57 patients (13 IF and 44 CF) with a mean age of 61.63 ±â€Š12.1 years. Chest x-ray, electrocardiogram, and echocardiogram were performed to classify the clinical forms.The CF group had a higher number of individuals with metabolic syndrome components blood pressure altered, while more participants in the CF group with LVD had low high-density lipoprotein (HDL) levels. The IF group had more participants with a higher waist-to-hip ratio (WHR). No significant difference was observed between metabolic syndrome, cytokine and adipocytokine level, and clinical forms of the disease or in relation to LVD.Individuals with the IF showed metabolic and immunological profiles compatible with increased disease control, whereas those with CF showed marked inflammatory immune response.


Assuntos
Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Adiponectina/análise , Adiponectina/sangue , Idoso , Análise de Variância , Biomarcadores/análise , Biomarcadores/sangue , Feminino , Cardiopatias/imunologia , Cardiopatias/metabolismo , Humanos , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-17/análise , Interleucina-17/biossíntese , Interleucina-33/análise , Interleucina-33/sangue , Leptina/análise , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Resistina/análise , Resistina/sangue , Estatísticas não Paramétricas
2.
PLoS Negl Trop Dis ; 14(9): e0008667, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32986710

RESUMO

Digestive and cardiodigestive forms of Chagas' disease are observed in 2% to 27% of the patients, depending on their geographic location, Trypanosoma cruzi strain and immunopathological responses. The aim of this work was to evaluate the role of NOD2 innate immune receptor in the pathogenesis of the digestive system in Chagas' disease. Patients with digestive form of the disease showed lower mRNA expression of NOD2, higher expression of RIP2 and α-defensin 6, compared to indeterminate form, detected by Real-time PCR in peripheral blood mononuclear cells. In addition, there was a negative correlation between the expression of NOD2 and the degree of dilation of the esophagus, sigmoid and rectum in those patients. The infection of NOD2-/- mice with T. cruzi strain isolated from the digestive patient induced a decrease in intestinal motility. Histopathological analysis of the colon and jejunum of NOD2-/- and wild type C57BL/6 animals revealed discrete inflammatory foci during the acute phase of infection. Interestingly, during the chronic phase of the infection there was inflammation and hypertrophy of the longitudinal and circular muscular layer more pronounced in the colon and jejunum from NOD2-/- animals, when compared to wild type C57BL/6 mice. Together, our results suggest that NOD2 plays a protective role against the development of digestive form of Chagas' disease.


Assuntos
Doença de Chagas/imunologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/imunologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Trypanosoma cruzi/imunologia , Adolescente , Adulto , Idoso , Animais , Brasil , Doença de Chagas/patologia , Colo/microbiologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Adulto Jovem , alfa-Defensinas/genética , alfa-Defensinas/metabolismo
3.
PLoS Negl Trop Dis ; 14(9): e0008608, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925918

RESUMO

The receptor Signaling Lymphocyte-Activation Molecule Family 1 (SLAMF1) controls susceptibility to Infection by the lethal Trypanosoma cruzi Y strain. To elucidate whether genetic diversity of the parasite was related with disease susceptibility, we further analyzed the role of SLAMF1 using 6 different Trypanosoma cruzi strains including Y. The interaction of SLAMF1 receptor with T. cruzi was evidenced by fluorescence microscopy, flow cytometry and quantitative PCR. All the strains, except VFRA, showed a decrease in parasite load in infected macrophages in Slamf1-/- compared to BALB/c. In macrophages gene expression NADPH oxidase (NOX2), and reactive oxygen species (ROS) production increased in Slamf1-/- compared to BALB/c in 5 out of 6 strains. However, Slamf1-/-macrophages infected with VFRA strain exhibited a divergent behavior, with higher parasite load, lower NOX2 expression and ROS production compared to BALB/c. Parasitological and immunological studies in vivo with Y strain showed that in the absence of SLAMF1 the immune response protected mice from the otherwise lethal Y infection favoring a proinflammatory response likely involving CD4, CD8, dendritic cells and classically activated macrophages. In the case of VFRA, no major changes were observed in the absence of SLAMF1. Thus, the results suggest that the T. cruzi affects SLAMF1-dependent ROS production, controlling parasite replication in macrophages and affecting survival in mice in a strain-dependent manner. Further studies will focus in the identification of parasite molecules involved in SLAMF1 interaction to explain the immunopathogenesis of the disease.


Assuntos
Macrófagos/parasitologia , Espécies Reativas de Oxigênio/metabolismo , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Trypanosoma cruzi/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Doença de Chagas/imunologia , Chlorocebus aethiops , Células Dendríticas/imunologia , Suscetibilidade a Doenças/imunologia , Células HEK293 , Coração/parasitologia , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocárdio/patologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Carga Parasitária , Células Vero
4.
PLoS Negl Trop Dis ; 14(6): e0008414, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574175

RESUMO

Chemokine receptor type 3 (CXCR3) plays an important role in CD8+ T cells migration during intracellular infections, such as Trypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental to T. cruzi-specific CD8+ T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutely T. cruzi-infected mice decreased the number of specific CD8+ T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8+ T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8+ T cells interacted with plasmacytoid dendritic cells during infection by T. cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8+ T cells. Understanding which molecules and mechanisms guide CD8+ T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role in T. cruzi infection control.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Quimiocinas/metabolismo , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Receptores CXCR3/metabolismo , Trypanosoma cruzi/imunologia , Animais , Movimento Celular , Doença de Chagas/parasitologia , Citoplasma/metabolismo , Citoplasma/parasitologia , Modelos Animais de Doenças , Feminino , Coração , Controle de Infecções , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia
5.
PLoS Negl Trop Dis ; 14(4): e0007717, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32302312

RESUMO

BACKGROUND: The long term and complex nature of Chagas disease in humans has restricted studies on vaccine feasibility. Animal models also have limitations due to technical difficulties in monitoring the extremely low parasite burden that is characteristic of chronic stage infections. Advances in imaging technology offer alternative approaches that circumvent these problems. Here, we describe the use of highly sensitive whole body in vivo imaging to assess the efficacy of recombinant viral vector vaccines and benznidazole-cured infections to protect mice from challenge with Trypanosoma cruzi. METHODOLOGY/PRINCIPAL FINDINGS: Mice were infected with T. cruzi strains modified to express a red-shifted luciferase reporter. Using bioluminescence imaging, we assessed the degree of immunity to re-infection conferred after benznidazole-cure. Those infected for 14 days or more, prior to the onset of benznidazole treatment, were highly protected from challenge with both homologous and heterologous strains. There was a >99% reduction in parasite burden, with parasites frequently undetectable after homologous challenge. This level of protection was considerably greater than that achieved with recombinant vaccines. It was also independent of the route of infection or size of the challenge inoculum, and was long-lasting, with no significant diminution in immunity after almost a year. When the primary infection was benznidazole-treated after 4 days (before completion of the first cycle of intracellular infection), the degree of protection was much reduced, an outcome associated with a minimal T. cruzi-specific IFN-γ+ T cell response. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that a protective Chagas disease vaccine must have the ability to eliminate parasites before they reach organs/tissues, such as the GI tract, where once established, they become largely refractory to the induced immune response.


Assuntos
Doença de Chagas/imunologia , Doença de Chagas/prevenção & controle , Imunidade Heteróloga , Vacinas Protozoárias/imunologia , Trypanosoma cruzi/imunologia , Vacinação/métodos , Animais , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , Vacinas Protozoárias/administração & dosagem , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
6.
Trends Parasitol ; 36(4): 368-381, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32191851

RESUMO

To successfully infect, Trypanosoma cruzi evades and modulates the host immune response. T. cruzi calreticulin (TcCalr) is a multifunctional, endoplasmic reticulum (ER)-resident chaperone that, translocated to the external microenvironment, mediates crucial host-parasite interactions. TcCalr binds and inactivates C1 and mannose-binding lectin (MBL)/ficolins, important pattern- recognition receptors (PRRs) of the complement system. Using an apoptotic mimicry strategy, the C1-TcCalr association facilitates the infection of target cells. T. cruzi infection also seems to confer protection against tumorigenesis. Thus, recombinant TcCalr has important antiangiogenic properties, detected in vitro, ex vivo, and in ovum, most likely contributing at least in part, to its antitumor properties. Consequently, TcCalr is useful for investigating key issues of host-parasite interactions and possible new immunological/pharmacological interventions in the areas of Chagas' disease and experimental cancer.


Assuntos
Calreticulina/imunologia , Carcinogênese/imunologia , Doença de Chagas/complicações , Doença de Chagas/imunologia , Interações Hospedeiro-Parasita/imunologia , Neoplasias/etiologia , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Humanos , Evasão da Resposta Imune/imunologia , Neoplasias/imunologia , Trypanosoma cruzi/fisiologia , Fatores de Virulência/imunologia
7.
Sci Rep ; 10(1): 5294, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210339

RESUMO

The detection of pathogen-specific antibodies remains a cornerstone of clinical diagnostics. Yet, many test exhibit undesirable performance or are completely lacking. Given this, we developed serum epitope repertoire analysis (SERA), a method to rapidly discover conserved, pathogen-specific antigens and their epitopes, and applied it to develop an assay for Chagas disease caused by the protozoan parasite Trypanosoma cruzi. Antibody binding peptide motifs were identified from 28 Chagas repertoires using a bacterial display random 12-mer peptide library and next-generation sequencing (NGS). Thirty-three motifs were selected and mapped to candidate Chagas antigens. In a blinded validation set (n = 72), 30/30 Chagas were positive, 30/30 non-Chagas were negative, and 1/12 Leishmania sp. was positive. After unblinding, a Leishmania cross-reactive epitope was identified and removed from the panel. The Chagas assay exhibited 100% sensitivity (30/30) and specificity (90/90) in a second blinded validation set including individuals with other parasitic infections. Amongst additional epitope repertoires with unknown Chagas serostatus, assay specificity was 99.8% (998/1000). Thus, the Chagas assay achieved a combined sensitivity and specificity equivalent or superior to diagnostic algorithms that rely on three separate tests to achieve high specificity. NGS-based serology via SERA provides an effective approach to discover antigenic epitopes and develop high performance multiplex serological assays.


Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Doença de Chagas/sangue , Doença de Chagas/diagnóstico , Epitopos/imunologia , Trypanosoma cruzi/imunologia , Adulto , Anticorpos Antiprotozoários/sangue , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Feminino , Humanos , Masculino , Biblioteca de Peptídeos
8.
J Leukoc Biol ; 107(4): 695-706, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32202341

RESUMO

In secondary lymphoid organs, pathogen-derived and endogenous danger molecules are recognized by pattern recognition receptors, leading to adaptive proinflammatory immune responses. This conceptual rule does not apply directly to the liver, as hepatic immune cells tolerate gut-derived bacterial molecules from the flora. Therefore, the recognition of danger and proinflammatory stimuli differs between the periphery and the liver. However, the tolerant nature of the liver must be overcome in the case of infections or cancer, for example. The central paradigm is the basis for danger recognition and the balance between inflammation and tolerance in the liver. Here, we observed functional integration, with activated peripheral T lymphocytes playing a role in the induction of a proinflammatory environment in the liver in the presence of Trypanosoma cruzi antigens. When only parasite extract was orally administered, it led to the up-regulation of hepatic tolerance markers, but oral treatment plus adoptively transferred activated splenic T lymphocytes led to a proinflammatory response. Moreover, treated/recipient mice showed increased levels of TNF, IFN-γ, IL-6, and CCL2 in the liver and increased numbers of effector and/or effector memory T lymphocytes and F4/80+ cells. There was a reduction in FoxP3+ Treg cells, NKT cells, and γδ T lymphocytes with increased liver damage in the presence of activated peripheral T cells. Our results show that the induction of a proinflammatory liver response against T. cruzi danger molecules is at least partially dependent on cooperation with activated peripheral T cells.


Assuntos
Antígenos de Protozoários/imunologia , Inflamação/patologia , Fígado/patologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Trypanosoma cruzi/imunologia , Transferência Adotiva , Animais , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Citocinas/metabolismo , Linfócitos Intraepiteliais/imunologia , Macrófagos do Fígado/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células T Matadoras Naturais/imunologia , Parasitos/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/parasitologia , Linfócitos T Reguladores/imunologia
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165707, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004621

RESUMO

Current understanding of key cellular pathways, which are activated by the interaction between T. cruzi and host immunity, is crucial for controlling T. cruzi infection and also for limiting the development of the immunopathological symptoms of Chagas´ disease. Here, we focus on recent advances in the knowledge of modulation of innate receptors such as TLRs and NLRs, especially NLRP3, by T. cruzi in different cells of the immune system. On the other hand, the modulation of macrophage activation may be instrumental in allowing parasite persistence and long-term host survival. In this sense, we discuss the importance of the metabolism of two amino acids: L-arginine and tryptophan, and evaluate the role of iNOS, arginase and IDO enzymes in the regulation of innate and adaptive immune response during this infection; and, finally, we also discuss how T. cruzi exploits the AhR, mTOR and Wnt signaling pathways to promote their intracellular replication in macrophages, thus evading the host's immune response.


Assuntos
Doença de Chagas/imunologia , Interações Hospedeiro-Parasita/imunologia , Transdução de Sinais/imunologia , Trypanosoma cruzi/imunologia , Imunidade Adaptativa , Animais , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/metabolismo , Arginina/imunologia , Arginina/metabolismo , Caspase 1/metabolismo , Doença de Chagas/parasitologia , Modelos Animais de Doenças , Vetores de Doenças , Humanos , Imunidade Inata , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Toll-Like/metabolismo , Triatoma/imunologia , Triatoma/parasitologia , Trypanosoma cruzi/metabolismo , Triptofano/imunologia , Triptofano/metabolismo
10.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31907197

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is a major public health issue. Limitations in immune responses to natural T. cruzi infection usually result in parasite persistence with significant complications. A safe, effective, and reliable vaccine would reduce the threat of T. cruzi infections; however, no suitable vaccine is currently available due to a lack of understanding of the requirements for induction of fully protective immunity. We established a T. cruzi strain expressing green fluorescent protein (GFP) under the control of dihydrofolate reductase degradation domain (DDD) with a hemagglutinin (HA) tag, GFP-DDDHA, which was induced by trimethoprim-lactate (TMP-lactate), which results in the death of intracellular parasites. This attenuated strain induces very strong protection against reinfection. Using this GFP-DDDHA strain, we investigated the mechanisms underlying the protective immune response in mice. Immunization with this strain led to a response that included high levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), as well as a rapid expansion of effector and memory T cells in the spleen. More CD8+ T cells differentiate to memory cells following GFP-DDDHA infection than after infection with a wild-type (WT) strain. The GFP-DDDHA strain also provides cross-protection against another T. cruzi isolate. IFN-γ is important in mediating the protection, as IFN-γ knockout (KO) mice failed to acquire protection when infected with the GFP-DDDHA strain. Immune cells demonstrated earlier and stronger protective responses in immunized mice after reinfection with T. cruzi than those in naive mice. Adoptive transfers with several types of immune cells or with serum revealed that several branches of the immune system mediated protection. A combination of serum and natural killer cells provided the most effective protection against infection in these transfer experiments.


Assuntos
Doença de Chagas/prevenção & controle , Vacinas Protozoárias/imunologia , Subpopulações de Linfócitos T/imunologia , Trypanosoma cruzi/imunologia , Animais , Doença de Chagas/imunologia , Modelos Animais de Doenças , Imunidade Celular , Fatores Imunológicos/metabolismo , Interferon gama/metabolismo , Camundongos , Vacinas Protozoárias/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
11.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165692, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972227

RESUMO

Many important pathogen-host interactions rely on highly specific carbohydrate binding events. In the case of the protozoan Trypanosoma cruzi, the causative agent of Chagas disease, glycointeractions involving sialic acid (SA) residues are pivotal for parasite infectivity, escape from immune surveillance and pathogenesis. Though unable to synthesize SA de novo, T. cruzi displays a unique trans-Sialidase (TS) enzyme, which is able to cleave terminal SA residues from host donor glycoconjugates and transfer them onto parasite surface mucins, thus generating protective/adhesive structures. In addition, this parasite sheds TS into the bloodstream, as a way of modifying the surface SA signature, and thereby the signaling/functional properties of mammalian host target cells on its own advantage. Here, we discuss the pathogenic aspects of T. cruzi TS: its molecular adaptations, the multiplicity of interactions in which it is involved during infections, and the array of novel and appealing targets for intervention in Chagas disease provided by TS-remodeled sialoglycophenotypes.


Assuntos
Doença de Chagas/imunologia , Glicoproteínas/metabolismo , Interações Hospedeiro-Parasita/imunologia , Neuraminidase/metabolismo , Polissacarídeos/imunologia , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Glicoproteínas/imunologia , Humanos , Evasão da Resposta Imune , Neuraminidase/imunologia , Polissacarídeos/química , Polissacarídeos/metabolismo , Proteínas de Protozoários/imunologia , Ácidos Siálicos/química , Ácidos Siálicos/imunologia , Ácidos Siálicos/metabolismo , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/imunologia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo
12.
Clin Immunol ; 212: 108346, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31954803

RESUMO

Previous studies showed that circulating autoantibodies against M2 muscarinic receptors (anti-M2R Ab) are associated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD). Here we investigated whether the exposure of M2R to such antibodies could impair agonist-induced receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced Gi protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2R internalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation. Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.


Assuntos
Autoanticorpos/imunologia , Doenças do Sistema Nervoso Autônomo/imunologia , Doença de Chagas/imunologia , Receptor Muscarínico M2/imunologia , Adulto , Idoso , Regulação Alostérica , Autoanticorpos/metabolismo , Autoanticorpos/farmacologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/metabolismo , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Carbacol/farmacologia , Doença de Chagas/complicações , Doença de Chagas/metabolismo , Doença de Chagas/fisiopatologia , Agonistas Colinérgicos/farmacologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Muscarínico M2/efeitos dos fármacos , Receptor Muscarínico M2/metabolismo , beta-Arrestina 1/metabolismo
13.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165706, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987839

RESUMO

Host resistance during infection with Trypanosoma cruzi, and other protozoans, is dependent on a balanced immune response. Robust immunity against these pathogens requires of the concerted action of many innate and adaptive cell populations including macrophages, neutrophils, dendritic cells, CD4+, and CD8+ T cells and B cells among others. Indeed, during most protozoan infections only a balanced production of inflammatory (TH1) and anti-inflammatory (TH2/regulatory) cytokines will allow the control of parasite spreading without compromising host tissue integrity. The description of TH17 cells, a novel effector helper T cell lineage that produced IL-17 as signature cytokine, prompted the revision of our knowledge about the mechanisms that mediate protection and immunopathology during protozoan infections. In this manuscript we discuss the general features of IL-17 mediated immune responses as well as the cellular sources, effector mechanisms and overall role of IL-17 in the immune response to T. cruzi and other protozoan infections.


Assuntos
Doença de Chagas/imunologia , Interações Hospedeiro-Parasita/imunologia , Imunidade Celular , Interleucina-17/metabolismo , Trypanosoma cruzi/imunologia , Animais , Antígenos de Protozoários/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Doença de Chagas/parasitologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata , Interleucina-17/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165629, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816438

RESUMO

One of the greatest challenges in Chagas disease research is the search for tools that will enable the assessment of pharmacological treatment efficacy. A recently described set of serological biomarkers composed of four parasite antigens and established criteria of treatment efficacy allowed the evaluation of the impact of benznidazole treatment a short/medium time after the treatment. In addition, cellular immunological parameters have also been described as potential indicators of the treatment response. The cytotoxic CD8+ T cells specific to five epitopes in the PFR2, PFR3, TcCA-2 and KMP11 antigens have been analysed, and these epitopes have been shown to be recognized, processed and presented in the context of a natural T. cruzi infection. In the present manuscript, we characterized these antigen-specific CD8+ T cells in indeterminate chronic Chagas disease patients both before and after (from 11 to 28 months) benznidazole treatment. The results indicate that there is a differential memory CD8+ T cell profile depending on the antigenic epitope and that the benznidazole treatment modulates the memory, differentiation and senescence phenotypes of the epitope-specific CD8+ T cells. Moreover, in these patients, the reactivity of sera against the referred set of biomarkers was evaluated. The data obtained show that the patients who met the established therapeutic efficacy criteria presented a differential phenotypic profile of the antigen-specific CD8+ T cells even prior to treatment compared to the patients who did not meet the therapeutic efficacy criteria, and this behaviour is associated with a better functionality of these CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/imunologia , Epitopos/imunologia , Nitroimidazóis/uso terapêutico , Adulto , Biomarcadores/sangue , Linfócitos T CD8-Positivos/parasitologia , Doença de Chagas/parasitologia , Citocinas/imunologia , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/parasitologia , Masculino , Fenótipo , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/imunologia
15.
Cell Immunol ; 348: 103974, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31879029

RESUMO

Chronic infection by Trypanosoma cruzi decreases T cell proliferation and it is most likely accompanied by changes in signals required for activation. We assessed the effect of T. cruzi antigens on mitogen-induced proliferation of T cells from uninfected individuals and the association with the expression of molecules involved in antigen presentation, T cell costimulation and activation, and cytokine production. T. cruzi antigen exposure reduced mitogen-induced proliferation of CD4+ and CD8+ T cells in PBMC cultures, but only reduced mitogen-induced proliferation in the CD4+ T cells from sorted cell cultures cocultured with antigen-pulsed CD3- cells. CD40/CD80 and CD86 expression were reduced in antigen-pulsed DCs and monocytes, respectively. TNF-α, IL-10 and CCL17 levels were increased in cultures with antigen-pulsed CD3- cells, while CD3ζ chain expression was reduced in T cells from cultures with antigen. Our findings suggest that T. cruzi could alter T cell proliferation indirectly by downregulating costimulatory molecules and inducing the secretion of IL-10 and directly by decreasing TCR signaling.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos de Protozoários/imunologia , Complexo CD3/imunologia , Doença de Chagas/imunologia , Linfócitos T/imunologia , Adulto , Proliferação de Células/fisiologia , Feminino , Humanos , Ativação Linfocitária/imunologia , Masculino , Transdução de Sinais/imunologia , Trypanosoma cruzi
16.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165642, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31866417

RESUMO

Studies in mice undergoing acute Trypanosoma cruzi infection and patients with Chagas disease, led to identify several immune-neuroendocrine disturbances and metabolic disorders. Here, we review relevant findings concerning such abnormalities and discuss their possible influence on disease physiopathology.


Assuntos
Doença de Chagas/imunologia , Doenças Metabólicas/imunologia , Células Neuroendócrinas/imunologia , Trypanosoma cruzi/imunologia , Animais , Doença de Chagas/parasitologia , Humanos , Doenças Metabólicas/parasitologia , Células Neuroendócrinas/parasitologia
17.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165628, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809789

RESUMO

Patients infected by Trypanosoma cruzi are typically diagnosed by detecting specific antibodies in serological assays. Persistence of the parasitic infection increases the risk of morbidity and mortality. There are indications that anti-parasitic therapies help to reduce these risks when comparing treated and untreated populations. However, at present, treatment efficacy cannot be properly evaluated on an individual patient basis by available laboratory methods. To monitor parasite clearance, it is essential to change the paradigm of serological methods: analyzing the broad spectrum of antibody diversity is more informative about clinical status than conventional serology tests designed merely for global detection of antibodies.


Assuntos
Doença de Chagas/imunologia , Trypanosoma cruzi/imunologia , Animais , Humanos , Testes Sorológicos/métodos
18.
Clin Exp Immunol ; 199(2): 216-229, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31593356

RESUMO

Galectin-3 is the best-characterized member of galectins, an evolutionary conserved family of galactoside-binding proteins that play central roles in infection and immunity, regulating inflammation, cell migration and cell apoptosis. Differentially expressed by cells and tissues with immune privilege, they bind not only to host ligands, but also to glycans expressed by pathogens. In this regard, we have previously shown that human galectin-3 recognizes several genetic lineages of the protozoan parasite Trypanosoma cruzi, the causal agent of Chagas' disease or American trypanosomiasis. Herein we describe a molecular mechanism developed by T. cruzi to proteolytically process galectin-3 that generates a truncated form of the protein lacking its N-terminal domain - required for protein oligomerization - but still conserves a functional carbohydrate recognition domain (CRD). Such processing relies on specific T. cruzi proteases, including Zn-metalloproteases and collagenases, and ultimately conveys profound changes in galectin-3-dependent effects, as chemical inhibition of parasite proteases allows galectin-3 to induce parasite death in vitro. Thus, T. cruzi might have established distinct mechanisms to counteract galectin-3-mediated immunity and microbicide properties. Interestingly, non-pathogenic T. rangeli lacked the ability to cleave galectin-3, suggesting that during evolution two genetically similar organisms have developed different molecular mechanisms that, in the case of T. cruzi, favoured its pathogenicity, highlighting the importance of T. cruzi proteases to avoid immune mechanisms triggered by galectin-3 upon infection. This study provides the first evidence of a novel strategy developed by T. cruzi to abrogate signalling mechanisms associated with galectin-3-dependent innate immunity.


Assuntos
Doença de Chagas/imunologia , Galectina 3/imunologia , Imunidade Inata , Metaloproteases/imunologia , Proteólise , Proteínas de Protozoários/imunologia , Trypanosoma cruzi/imunologia , Doença de Chagas/patologia , Galectina 3/química , Humanos , Metaloproteases/química , Domínios Proteicos , Proteínas de Protozoários/química
19.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165592, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678157

RESUMO

Damaged cells release the pro-inflammatory signal ATP, which is degraded by the ectonucleotidases CD39 and CD73 to the anti-inflammatory mediator adenosine (ADO). The balance between ATP/ADO is known to determine the outcome of inflammation/infection. However, modulation of the local immune response in different tissues due to changes in the balance of purinergic metabolites has yet to be investigated. Here, we explored the contribution of CD73-derived ADO on the acute immune response against Trypanosoma cruzi parasite, which invades and proliferates within different target tissues. Deficiency of CD73 activity led to an enhanced cardiac microbicidal immune response with an augmented frequency of macrophages with inflammatory phenotype and increased CD8+ T cell effector functions. The increment of local inducible nitric oxide (NO) synthase (iNOS)+ macrophages and the consequent rise of myocardial NO production in association with reduced ADO levels induced protection against T. cruzi infection as observed by the diminished cardiac parasite burden compared to their wild-type (WT) counterpart. Unexpectedly, parasitemia was substantially raised in CD73KO mice in comparison with WT mice, suggesting the existence of tissue reservoir/s outside myocardium. Indeed, CD73KO liver and visceral adipose tissue (VAT) showed increased parasite burden associated with a reduced ATP/ADO ratio and the lack of substantial microbicidal immune response. These data reveal that the purinergic system has a tissue-dependent impact on the host immune response against T. cruzi infection.


Assuntos
5'-Nucleotidase/imunologia , Tecido Adiposo/imunologia , Doença de Chagas/imunologia , Miocárdio/imunologia , Trypanosoma cruzi/imunologia , Trifosfato de Adenosina/imunologia , Tecido Adiposo/parasitologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carotenoides/imunologia , Doença de Chagas/parasitologia , Modelos Animais de Doenças , Feminino , Coração/parasitologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Oxigenases/imunologia
20.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165591, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678160

RESUMO

Trypanos o ma cruzi (T. cruzi or Tc) is the causative agent of Chagas disease (CD). It is common for patients to suffer from non-specific symptoms or be clinically asymptomatic with acute and chronic conditions acquired through various routes of transmission. The expecting women and their fetuses are vulnerable to congenital transmission of Tc. Pregnant women face formidable health challenges because the frontline antiparasitic drugs, benznidazole and nifurtimox, are contraindicated during pregnancy. However, it is worthwhile to highlight that newborns can be cured if they are diagnosed and given treatment in a timely manner. In this review, we discuss the pathogenesis of maternal-fetal transmission of Tc and provide a justification for the investment in the development of vaccines against congenital CD.


Assuntos
Doença de Chagas/imunologia , Doença de Chagas/patologia , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Trypanosoma cruzi/imunologia , Vacinas/imunologia , Animais , Doença de Chagas/parasitologia , Feminino , Feto/imunologia , Feto/parasitologia , Feto/patologia , Humanos , Recém-Nascido , Gravidez
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