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delayed type hypersensitivity skin test in mice with single infection (24 h). A: focal, mild, diffuse polymorphonuclear cells infiltration around venules and arterioles and diffuse mononuclear infiltration; B-D: triple infection, lesions after 48 h are represented by diffuse mononuclear infiltration in the dermis and polymorphonuclear cells involving the vessels (venules and arterioles) and nervous fibres (400X).
Source publication
Re-infections with Trypanosoma cruzi are an aggravating factor for Chagas disease morbidity. The Colombian strain of T. cruzi represents multiclonal populations formed by clonally propagating organisms with different tropisms and degrees of virulence. In the present study, the influence of successive inoculations with clones of the Colombian strain...
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Context 1
... -(i) Skin test in mice with single infection: mice with a single chronic in- fection at 24 h and 48 h after antigen injection showed focal and mild diffuse polymorphonuclear neutrophil infiltrates and diffuse mononuclear cell infiltration in the dermis and subdermic conjunctive tissue involving small vessels (venules and arterioles) (p < 0.05) (Fig. 6A); (ii) skin test in mice with triple infection: the inflammatory response was more robust within 24 h with increased myositis and poly- Fig. 2: serological levels of immunoglobulins in the acute and chronic phases of single and triple infection in mice infected with the clones Col-C1 (high virulence), Col-C8 (medium virulence) and ...
Context 2
... and controls. morphonuclear cell infiltration involving the vessels and nervous fibres. These lesions extended to the subdermal tissue with diffuse mononuclear cell infiltration and the involvement of vessels and cutaneous annexes. After 48 h, the lesions were similar but less intense than those observed 24 h post antigen injection (p < 0.0008) (Fig. ...
Similar publications
La infección por Trypanosoma cruzi causa la enfermedad de Chagas, la cual presenta una fase aguda en la que la activación del sistema inmunitario ayuda a controlar el parásito. No obstante, el parásito puede persistir en bajos niveles y producir una fase crónica en la cual el 70 % de los individuos infectados permanece asintomático, en tanto que lo...
Citations
... CD8+ (ANDRADE et al., 2000;ANDRADE, 1999;GUERREIRO et al., 2015;PORTELLA e ANDRADE, 2009;MARTIN et al., 2010).Diversos estudos clínicos e experimentais chamam a atenção para o papel sinérgico entre o tratamento com Benzonidazol (N-benzyl-2-nitroimidazole acetamida) e o sistema imunológico (OLIVIEIRI et al., 2006;OLIVIERI et al., 2002;VIOTTI et al., 2011). OLIVIERI et al. (2006), estudando o papel do tratamento com o Benzonidazol sobre a resposta imune de camundongos infectados com uma cepa susceptível e, a diminuição nas taxas de apoptose em linfócitos duplo positivo CD4 + /CD8 + no timo, verificaram menores índices de apoptose dessas células, nos camundongos infectados e tratados em relação aos camundongos infectados não tratados, correlacionando embora que parcialmente, a preservação da homeostasia do timo ao tratamento com Benzonidazol.Entre os fatores que podem estar envolvidos no maior ou menor grau de resistência ao tratamento, está a resposta imunológica determinada no animal experimental por diferentes cepas, tendo sido evidenciado uma melhor capacidade modulatória nas cepas mais resistentes (MICHAILOWSKY et al., 2001). ...
... Esses estudos demonstram serem essas citocinas (IFN-ƴ e TNF-α) importantes no recrutamento de populações inflamatórias e na geração de lesões. GUERREIRO et al., (2015), estudando a resposta imunológica em camundongos infectados pela cepa Colombiana resistente e de seus clones, sobre as lesões no miocárdio e no músculo esquelético, demonstraram extensos infiltrados inflamatórios difusos e focais compostos predominantemente de mononucleares. DOS SANTOS et al. (2008) estudando a resistência de populações de T. cruzi ao Benzonidazol, demonstraram que essas populações quando mantidas permanentemente através de passagens sucessivas in vivo ou in vitro, podem desencadear mecanismos de estabilidade/instabilidade fenotípicas tais como resistência a droga, bem como, aumento e diminuição da virulência e das lesões histopatológicas. ...
... Observar intensa miocardite difusa e focal (seta) e presença de necrose (A, B); presença miosite intensa difusa e focal (seta), áreas extensas de necrose e ninho grande ninho A miocardite e a miosite chagásica, observada na infecção pelo T. cruzi, e as lesões necrótico-inflamatórias focais e difusas de células cardíacas não-parasitadas e da musculatura esquelética, sugere a participação de mecanismos citotóxicos provenientes das citocinas liberadas pelas células do sistema imune são os geradores das lesões na fase aguda e tardia associados a imunopatogenia dessas lesões chagásicas. Estudos avaliando o perfil das lesões inflamatórias e das populações celulares no miocárdio e musculo esquelético, através da imunohistoquímica evidenciaram ampla destruição de fibras cardíacas com presença ou ausência de parasitismo, áreas necrótico-fibrosas, apoptose de miocélulas em associação com a presença de linfócitos T CD4+ e T CD8+, sendo essas células essenciais na imunoproteção e também na geração das lesões (ALVAREZ et al., 2008;ANDRADE, 2000;GUERREIRO et al., 2015;THÉ et al., 2013). Esses estudos corroboram com nossos achados quando analisamos as lesões no miocárdio e no musculo esquelético. ...
... Another relevant factor is the increase in domestic and international collaboration, which stimulates further research [15,[22][23][24]. Our findings revealed a high degree of domestic collaboration, especially in recent years, in response to the multidisciplinary nature of this clinical entity, which is relevant to tropical medicine, parasitology, cardiology, pathology, biochemistry and immunology, infectious diseases, physiology, microbiology and public health [25][26]. ...
... We also found MeSH terms detailing the follow-up of patients with cardiomyopathy, and the evolution of Chagas disease towards cardiomyopathy, which shows that these topics are still poorly understood [25,[40][41][42]. With regard to animal models, the related MeSH terms reflect an interest in understanding the immunoallergic and microbiological implications of Chagas disease and Chagas myocardiopathy [26,43]. ...
Background
Chagas cardiomyopathy is a serious and common complication of Chagas disease.
Methods
Through bibliometric and Social Network Analysis, we examined patterns of research on Chagas cardiomyopathy, identifying the main countries, authors, research clusters, and topics addressed; and measuring the contribution of different countries.
Results
We found 1932 documents on Chagas cardiomyopathy in the MEDLINE database. The most common document type was `journal article', accounting for 79.6% of the total (n =1538), followed by `review' (n = 217, 11.2%). The number of published records increased from 156 in 1980±1984 to 311 in 2010±2014. Only 2.5% were clinical trials. Brazil and the USA dominated the research, participating in 53.1% and 25.7%, respectively, of the documents. Other Latin American countries where Chagas is endemic contributed less, with Bolivia, where Chagas disease is most prevalent, producing only 1.8% of the papers. We observed a high rate of domestic collaboration (83.1% of the documents published in 2010±2016) and a lower but significant rate of international collaboration (32.5% in the same time period). Although clinical research dominated overall, the USA, Mexico and several countries in Europe produced a considerable body of basic research on animal models. We identified four main research clusters, focused on heart failure and dysfunction (physical symptoms, imaging techniques, treatment), and on myocarditis and parasitemia in animal models.
Conclusions
Research on Chagas cardiomyopathy increased over the study period. There were more clinical than basic studies, though very few of the documents were clinical trials. Brazil and the USA are currently leading the research on this subject, while some highly endemic countries, such as Bolivia, have contributed very little. Different approaches could help to redress this imbalance: encouraging researchers to conduct more clinical trials, launching international collaborations to help endemic countries contribute more, and strengthening links between basic and clinical research.
... The colon and blood samples from the Y/Y-infected mice showed reduced parasite loads than those from the DA/Y-infected mice. Previous reports suggest a positive correlation between the inflammatory infiltrate and the deterioration of cardiac function in infected and reinfected mice (Guerreiro et al., 2015). Although we also sought to establish a relationship between the parasite load and inflammatory infiltrate in tissue samples from Y/ Y-or DA/Y-infected mice, similar inflammatory infiltrate scores were found in the tissue samples from both groups. ...
Chagas disease (ChD) is a chronic infection caused by Trypanosoma cruzi. This highly diverse intracellular parasite is classified into seven genotypes or discrete typing units (DTUs) and they overlap in geographic ranges, vectors, and clinical characteristics. Although studies have suggested that ChD progression is due to a decline in the immune response quality, a direct relationship between T cell responses and disease outcome is still unclear. To investigate the relationship between parasite control and immune T cell responses, we used two distinct infection approaches in an animal model to explore the histological and parasitological outcomes and dissect the T cell responses in T. cruzi-infected mice. First, we performed single infection experiments with DA (TcI) or Y (TcII) T. cruzi strains to compare the infection outcomes and evaluate its relationship with the T cell response. Second, because infections with diverse T. cruzi genotypes can occur in naturally infected individuals, mice were infected with the Y or DA strain and subsequently reinfected with the Y strain. We found different infection outcomes in the two infection approaches used. The single chronic infection showed differences in the inflammatory infiltrate level, while mixed chronic infection by different T. cruzi DTUs showed dissimilarities in the parasite loads. Chronically infected mice with a low inflammatory infiltrate (DA-infected mice) or low parasitemia and parasitism (Y/Y-infected mice) showed increases in early-differentiated CD8⁺ T cells, a multifunctional T cell response and lower expression of inhibitory receptors on CD8⁺ T cells. In contrast, infected mice with a high inflammatory infiltrate (Y-infected mice) or high parasitemia and parasitism (DA/Y-infected mice) showed a CD8⁺ T cell response distinguished by an increase in late-differentiated cells, a monofunctional response, and enhanced expression of inhibitory receptors. Overall, our results demonstrated that the infection outcomes caused by single or mixed T. cruzi infection with different genotypes induce a differential immune CD8⁺ T cell response quality. These findings suggest that the CD8⁺ T cell response might dictate differences in the infection outcomes at the chronic T. cruzi stage. This study shows that the T cell response quality is related to parasite control during chronic T. cruzi infection.
... Some authors evaluated the cellular immune response of laboratory animals (mice, rabbits) infected with T. cruzi or other Trypanosoma species using a delayed type hypersensitivity test [30][31][32][33][34] . Mansfield and Kreier 33 described positive skin test reactions of the Arthus type (type III hypersensitivity reactions) in rabbits infected with T. congolense. ...
Trypanosoma equiperdum is the causative agent of dourine, a parasitic venereal disease of equids. In this work, rabbits were infected with T. equiperdum strain OVI; serological tests (complement fixation test, ELISA and immunoblotting), used for the diagnosis of dourine in horses, were applied to study rabbit humoral immune response and to characterise T. equiperdum antigen pattern recognised by antibodies from infected rabbits. Moreover a protein extract of T. equiperdum strain OVI was produced and tested in skin tests on infected rabbits to detect the cell-mediated response induced by T. equiperdum, in order to evaluate its use in the field diagnosis of dourine. Sera of infected rabbits recognized in immunoblotting Trypanosoma protein bands with molecular weight below 37 kDa, providing a serological response comparable with that already observed in dourine infected horses. Moreover the trypanosome protein extract was capable to produce in vivo delayed-type hypersensitivity (DHT Type IV) in rabbits and proved itself to be non-toxic and non-sensitizing.
... Here, T. cruzi infection induced a mononuclear inflammatory infiltrate that was potentially related to the presence of the parasite in tissues, as it was observed in nearly all of the colon and heart tissue samples obtained from infected mice. Additionally, high parasite loads were observed in colon, heart, liver, and skeletal muscle tissues with moderate inflammatory infiltrate obtained from mice with acute and chronic infections compared with those with low or absent inflammatory infiltrate, suggesting that our experimental model is similar to that of other studies (54,67). As it was to be expected, reticulotropic strains, such as Y strain, might be involved in increased inflammatory infiltrates in liver and spleen tissues and causes pathology as reported previously (57,58), but to evaluate the pathological forms of experimental ChD, is important to implement other methodological approaches, such as the measurement of heart rate or the identification of fibrosis in tissue samples (57,60,68). ...
Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi, represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20–40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi-infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi-infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi-infected mice. Acute ChD induced a high antigen-specific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes the dysfunctionality of T cells, and these changes might correlate with ChD progression. Thus, these results constitute a model that will facilitate an in-depth search for immune markers and correlates of protection, as well as long-term studies of new immunotherapy strategies for ChD.
... Another relevant factor is the increase in domestic and international collaboration, which stimulates further research [15,[22][23][24]. Our findings revealed a high degree of domestic collaboration, especially in recent years, in response to the multidisciplinary nature of this clinical entity, which is relevant to tropical medicine, parasitology, cardiology, pathology, biochemistry and immunology, infectious diseases, physiology, microbiology and public health [25][26]. ...
... We also found MeSH terms detailing the follow-up of patients with cardiomyopathy, and the evolution of Chagas disease towards cardiomyopathy, which shows that these topics are still poorly understood [25,[40][41][42]. With regard to animal models, the related MeSH terms reflect an interest in understanding the immunoallergic and microbiological implications of Chagas disease and Chagas myocardiopathy [26,43]. ...
Background
Chagas cardiomyopathy is a serious and common complication of Chagas disease.
Methods
Through bibliometric and Social Network Analysis, we examined patterns of research on Chagas cardiomyopathy, identifying the main countries, authors, research clusters, and topics addressed; and measuring the contribution of different countries.
Results
We found 1932 documents on Chagas cardiomyopathy in the MEDLINE database. The most common document type was ‘journal article’, accounting for 79.6% of the total (n = 1538), followed by ‘review’ (n = 217, 11.2%). The number of published records increased from 156 in 1980–1984 to 311 in 2010–2014. Only 2.5% were clinical trials. Brazil and the USA dominated the research, participating in 53.1% and 25.7%, respectively, of the documents. Other Latin American countries where Chagas is endemic contributed less, with Bolivia, where Chagas disease is most prevalent, producing only 1.8% of the papers. We observed a high rate of domestic collaboration (83.1% of the documents published in 2010–2016) and a lower but significant rate of international collaboration (32.5% in the same time period). Although clinical research dominated overall, the USA, Mexico and several countries in Europe produced a considerable body of basic research on animal models. We identified four main research clusters, focused on heart failure and dysfunction (physical symptoms, imaging techniques, treatment), and on myocarditis and parasitemia in animal models.
Conclusions
Research on Chagas cardiomyopathy increased over the study period. There were more clinical than basic studies, though very few of the documents were clinical trials. Brazil and the USA are currently leading the research on this subject, while some highly endemic countries, such as Bolivia, have contributed very little. Different approaches could help to redress this imbalance: encouraging researchers to conduct more clinical trials, launching international collaborations to help endemic countries contribute more, and strengthening links between basic and clinical research.
... cruzi chemotherapy, models using pathogenic strains with low virulence are a more rational strategy [60,61]. Based on these latter models, the chances of instilling morphological, electrical, and mechanical changes typical of Chagas' cardiomyopathy are enhanced [61][62][63]. Because the parasite strains used were aligned with the phases of interest in Chagas disease, the analyzed studies exhibited an important element of methodological consistence, with a positive reflection on construct validity. ...
Due to the rudimentary antioxidant defenses in Trypanosoma cruzi , disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β -adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro , and in vivo findings indicated that the anti- T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.
... This genetic heterogeneity means that dissimilar outcomes from reinfection experiments may reflect differences in parasite virulence or in the host immune response to the different parasite genotypes utilised. While the use of reference or highly utilised genotypes such as the Y (Andrade et al., 2006;Reis Machado et al., 2014), Tulahuen (Bustamante et al., 2007) and Colombian strains (Guerreiro et al., 2015) in previous reinfection studies was useful in order for comparisons to be drawn between studies, more studies involving diverse and previously uncharacterised genotypes are also required to expand our knowledge. ...
The progression of Chagas disease (CD) varies significantly from host to host and is affected by multiple factors. In particular, mixed strain infections and reinfections have the potential to exacerbate disease progression subsequently affecting clinical management of patients with CD. Consequently, an associated reduction in therapeutic intervention and poor prognosis may occur due to this exacerbated disease state.
This study investigated the effects of mixed strain infections and reinfection with Trypanosoma cruzi in mice, using two isolates from different discrete typing units, TcI (C8 clone 1) and TcIV (10R26). There were no significant differences in mortality rate, body weight or body condition among mice infected with either C8 clone 1, 10R26, or a mixture of both isolates. However, the parasite was found in a significantly greater number of host organs in mice infected with a mixture of isolates, and the histopathological response to infection was significantly greater in mice infected with C8 clone 1 alone, and C8 clone 1 + 10R26 mixed infections than in mice infected with 10R26 alone.
To investigate the effects of reinfection, mice received either a double exposure to C8 clone 1; a double exposure to 10R26; exposure to C8 clone 1 followed by 10R26; or exposure to 10R26 followed by C8 clone 1. Compared to single infection groups, mortality was significantly increased, while survival time, body weight and body condition were all significantly decreased across all reinfection groups, with no significant differences among these groups. The mortality rate over all reinfection groups was 63.6%, compared to 0% in single infection groups, however there was no evidence of a greater histopathological response to infection.
These results suggest firstly, that the C8 clone 1 isolate is more virulent than the 10R26 isolate, and secondly, that a more disseminated infection may occur with a mixture of isolates than with single isolates, although there is no evidence that mixed infections have a greater pathological effect. By contrast, reinfections do have major effects on host survivability and thus disease outcome. This confirms previous research demonstrating spontaneous deaths following reinfection, a phenomenon that to our knowledge has only been reported once before.
... This allowed us to design a mixed infection model that, both in terms of cardiac dysfunction as well as in its pathophysiological consequences, resembles what happens in chronic Chagas disease patients. In support of this, previous studies have shown that multiple infections lead to worsening of the inflammatory reaction (Bustamante et al., 2002(Bustamante et al., , 2003(Bustamante et al., , 2004Andrade et al., 2006) and immunopathological (Guerreiro et al., 2015) consequences. ...
Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation.
In this study we investigated whether the PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways.
Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease.
... This might stimulate finally the development of congenital-infection and -Chagas disease and jeopardize the fetus/neonate life. Interestingly, experimental data also highlight the pejorative role of re-infections in chronically infected animals, as well as in gestating dams which strongly increase pup mortality (Bustamante et al., 2002;Cencig et al., 2013;Guerreiro et al., 2015). This concept of an ecological interaction between repeated vector transmissions of parasites during pregnancy and a non-vector transmission in offspring might have practical consequences, since vector control programs in endemic Latin American areas might contribute to limit the severity of congenital Chagas disease. ...
The aim of this paper is to discuss the main ecological interactions between the parasite Trypanosoma cruzi and its hosts, the mother and the fetus, leading to the transmission and development of congenital Chagas disease. One or several infecting strains of T. cruzi (with specific features) interact with: (i) the immune system of a pregnant woman whom responses depend on genetic and environmental factors, (ii) the placenta harboring its own defenses, and, finally, (iii) the fetal immune system displaying responses also susceptible to be modulated by maternal and environmental factors, as well as his own genetic background which is different from her mother. The severity of congenital Chagas disease depends on the magnitude of such final responses. The paper is mainly based on human data, but integrates also complementary observations obtained in experimental infections. It also focuses on important gaps in our knowledge of this congenital infection, such as the role of parasite diversity vs host genetic factors, as well as that of the maternal and placental microbiomes and the microbiome acquisition by infant in the control of infection. Investigations on these topics are needed in order to improve the programs aiming to diagnose, manage and control congenital Chagas disease.
Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
