Ex vivo T-lymphocyte chemokine receptor phenotypes in patients with chronic Chagas disease

Miranda, Matheus Barbosa de; Melo, Adriene Siqueira de; Almeida, Mariana Silva; Marinho, Silvia Martins; Oliveira, Wilson de; Gomes, Yara de Miranda

doi:10.1590/0037-8682-0025-2017

Cited by 4 publications

(4 citation statements)

References 9 publications

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“…The inflammatory infiltrate present in the myocardium of CCC patients contains macrophages and B cells, but it is mainly composed of T-cells, primarily cytotoxic CD8 + T-cells followed by CD4 + T-cells (22). Although the recruitment mechanisms of these cells to the cardiac tissue of Chagas patients have not been clarified, the expression of chemotactic receptors that preferentially recruit inflammatory Th1 cells has been associated with severity of CCC (26)(27)(28). Exacerbated expression of inflammatory cytokines by circulating CD4 + , CD8 + and CD4-CD8-(double negative, DN) T-cells has also been associated with CCC, as well as with worse ventricular function in these patients (29)(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies

Neves

Koh

Silva

et al. 2022

Front. Cardiovasc. Med.

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Chronic Chagas cardiomyopathy (CCC) is one of the deadliest cardiomyopathies known and the most severe manifestation of Chagas disease, which is caused by infection with the parasite Trypanosoma cruzi. Idiopathic dilated cardiomyopathies (IDC) are a diverse group of inflammatory heart diseases that affect the myocardium and are clinically similar to CCC, often causing heart failure and death. While T-cells are critical for mediating cardiac pathology in CCC and IDC, the mechanisms underlying T-cell function in these cardiomyopathies are not well-defined. In this study, we sought to investigate the phenotypic and functional characteristics of T-cell subpopulations in CCC and IDC, aiming to clarify whether the inflammatory response is similar or distinct in these cardiomyopathies. We evaluated the expression of systemic cytokines, determined the sources of the different cytokines, the expression of their receptors, of cytotoxic molecules, and of molecules associated with recruitment to the heart by circulating CD4+, CD8+, and CD4-CD8- T-cells from CCC and IDC patients, using multiparameter flow cytometry combined with conventional and unsupervised machine-learning strategies. We also used an in silico approach to identify the expression of genes that code for key molecules related to T-cell function in hearts of patient with CCC and IDC. Our data demonstrated that CCC patients displayed a more robust systemic inflammatory cytokine production as compared to IDC. While CD8+ T-cells were highly activated in CCC as compared to IDC, CD4+ T-cells were more activated in IDC. In addition to differential expression of functional molecules, these cells also displayed distinct expression of molecules associated with recruitment to the heart. In silico analysis of gene transcripts in the cardiac tissue demonstrated a significant correlation between CD8 and inflammatory, cytotoxic and cardiotropic molecules in CCC transcripts, while no correlation with CD4 was observed. A positive correlation was observed between CD4 and perforin transcripts in hearts from IDC but not CCC, as compared to normal tissue. These data show a clearly distinct systemic and local cellular response in CCC and IDC, despite their similar cardiac impairment, which may contribute to identifying specific immunotherapeutic targets in these diseases.

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Section: Introductionmentioning

confidence: 99%

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies

Neves

Koh

Silva

et al. 2022

Front. Cardiovasc. Med.

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“…Nogueira and colleagues (Nogueira et al, 2012) demonstrated CCR5 expression on mononuclear cells in the myocardium of cardiac patients, but a comparative analysis was not carried out on biopsies from indeterminate asymptomatic patients. Miranda and colleagues (Miranda et al, 2017) did not find differences in the percentages of CCR5 + T-cells, both CD4 + and CD8 + , in peripheral blood from patients with different clinical forms of Chagas disease. Consistent with our findings, a previous study has shown a correlation between the CCR5 expression and the degree of heart function, such that the more severe the chronic chagasic cardiomyopathy, the lower the expression of CCR5 by circulating CD4 + and CD8 + T-cells (Talvani et al, 2004).…”

Section: Discussionmentioning

confidence: 90%

“…Therefore, the involvement of CCR5 in the recruitment of regulatory T-cells (Huehn and Hamann, 2005) indicates a dual role for this receptor, not only inducing but also resolving inflammatory response. Previous studies have tried to decipher whether CCR5 plays a role in the development of cardiac injuries or if it is a protective biomarker in Chagas disease (Talvani et al, 2004;Nogueira et al, 2012;de Oliveira et al, 2016;Miranda et al, 2017;Roffe et al, 2019). CCR5 + Tcells have been found in association with T. cruzi nests and antigens in heart tissue during murine acute infection, suggesting a direct anti-parasitic role (Marino et al, 2004) as well as its involvement in immunopathological mechanisms (Marino et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Functional Signatures of Peripheral Blood and Spleen Compartments of Cynomolgus Macaques Infected With T. cruzi: Associations With Cardiac Histopathological Characteristics

Sathler-Avelar

Vitelli-Avelar

Mattoso-Barbosa

et al. 2021

Front. Cell. Infect. Microbiol.

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We performed a detailed analysis of immunophenotypic features of circulating leukocytes and spleen cells from cynomolgus macaques that had been naturally infected with Trypanosoma cruzi, identifying their unique and shared characteristics in relation to cardiac histopathological lesion status. T. cruzi-infected macaques were categorized into three groups: asymptomatic [CCC(-)], with mild chronic chagasic cardiopathy [CCC(+)], or with moderate chronic chagasic cardiopathy [CCC(++)]. Our findings demonstrated significant differences in innate and adaptive immunity cells of the peripheral blood and spleen compartments, by comparison with non-infected controls. CCC(+) and CCC(++) hosts exhibited decreased frequencies of monocytes, NK and NKT-cell subsets in both compartments, and increased frequencies of activated CD8+ T-cells and GranA+/GranB+ cells. While a balanced cytokine profile (TNF/IL-10) was observed in peripheral blood of CCC(-) macaques, a predominant pro-inflammatory profile (increased levels of TNF and IFN/IL-10) was observed in both CCC(+) and CCC(++) subgroups. Our data demonstrated that cardiac histopathological features of T. cruzi-infected cynomolgus macaques are associated with perturbations of the immune system similarly to those observed in chagasic humans. These results provide further support for the validity of the cynomolgus macaque model for pre-clinical research on Chagas disease, and provide insights pertaining to the underlying immunological mechanisms involved in the progression of cardiac Chagas disease.

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“…In addition to innate immunity cells, CD4 + and CD8 + T lymphocytes reinforce parasitaemia control in acute infections (Ferraz et al ., 2009), contributing to the polarization of macrophages from Th1 cytokines (i.e. IFN- γ and TNF- α ) (Soares et al ., 2001; Miranda et al ., 2017). While CD4 + T cells exert immunomodulatory activities, CD8 + T lymphocytes exhibit direct cytotoxic activity that plays a central role against intracellular T. cruzi forms (amastigotes) (Cabral-Piccin et al ., 2016).…”

Section: Discussionmentioning

confidence: 99%

Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence

et al. 2019

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Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma cruzi infection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs on T. cruzi infections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The main in vitro findings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γ by T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed in T. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas’ disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.

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Ex vivo T-lymphocyte chemokine receptor phenotypes in patients with chronic Chagas disease

Cited by 4 publications

References 9 publications

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies

Phenotypic and Functional Signatures of Peripheral Blood and Spleen Compartments of Cynomolgus Macaques Infected With T. cruzi: Associations With Cardiac Histopathological Characteristics

Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence

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