Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies

Neves, Eula G. A.; Koh, Carolina Cattoni; Silva, José L. Padilha da; Passos, Lívia Silva Araújo; Villani, Fernanda Nobre Amaral; Santos, Janete Soares Coelho dos; Menezes, C. A. S.; Silva, Vicente R.; Tormin, Julia P.A.S.; Evangelista, Guilherme F.B.; Carvalho, Andréa Teixeira; Rocha, Manoel Otávio da Costa; Nascimento, Bruno Ramos; Gollob, Kenneth J.; Nunes, Maria do Carmo Pereira; Dutra, Walderez Ornelas

doi:10.1016/j.cyto.2021.155711

Cited by 12 publications

(13 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, dendrogram analysis showed that comparative expression of these molecules led to complete segregation between the groups. This data also reinforce the robust immune activation observed in CCC patients (50)(51)(52)(53). Network analysis showed that IL-6, IL-2, IL-15 and IL-10 emerged as node molecules with high centrality, suggesting a broad involvement of these immune molecules in CCC.…”

Section: Discussionsupporting

confidence: 81%

“…CD8 + cells display increased frequency of expression of TNFR1, TNF, IL-10, and IL-17 when compared to IDC, and CD4 + T-cells display increased expression of TNF and TNFR1 in IDC as compared to CCC. Increase expression of cytokines with different functional profiles observed in CCC is possibly related to a control mechanism for the intense inflammation observed in those patients (53,(62)(63)(64)(65)(66). Analysis of the ratio TNFR1/IL-10R revealed a predominantly inflammatory profile in CD8 + T-cells from CCC compared to IDC.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

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.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 94%

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…(39) Severity of CCC is correlated with high serum levels of proinflammatory (IL-6, IL-17, IFNγ, TNF) and regulatory (IL-4, IL-10, TGFβ) cytokines, chemokines (CCL2, CCL3, CCL5), and the inflammatory mediators NO. (9,10,11,40) Although most evidence lacks causal correlation, these data suggest that CCC is associated with a systemic inflammatory profile. Regardless the academic requirements for causa-effect relation in CCC patients, in experimental models subjected to therapeutic interventions with an adenovirus-based vaccine, (15) anti-TNF, (17) PTX, (18) TGFβ signaling blocker (27) or the trypanocidal drug Bz (41) the results support that lowering the systemic inflammatory cytokine levels plays beneficial role in CCC progression.…”

Section: Pathogenic Mechanisms and Modulatory Preclinical Strategy Te...mentioning

confidence: 91%

“…In addition, CCC severity was directly related to CK-MB activity serum levels, a biomarker of cardiomyocyte injury, and systemic inflammatory profile, with increased serum levels of tumor necrosis factor (TNF) and nitric oxide (NO), (12,14,15) thus replicating key aspects of chronic Chagas' heart disease. (8,9,10,11) In a proof-of-concept study to test TNF participation in CD pathogenesis, acutely T. cruzi-infected C3H/He mice were treated with the anti-TNF antibody infliximab. Survival was paralleled by reduced heart inflammation and tissue damage, without interference in parasite control, (16) placing TNF as a key cytokine in the pathogenesis of T. cruzi-elicited cardiac disease.…”

Section: Pathogenic Mechanisms and Modulatory Preclinical Strategy Te...mentioning

confidence: 99%

“…(8) Also, a systemic inflammatory profile, resembling a "cytokine storm" with increased serum concentrations of inflammatory (IL-6, TNF, IL-17, IFNγ) and regulatory (IL-4, IL-10, TGFβ) cytokines, and inflammatory mediators as nitric oxide (NO), is associated with the severity of Chagas' heart disease but absent in non-cardiopathic and indeterminate form CD patients. (8,9,10,11) Thus, in cardiopathic CD patients, low-grade parasite persistence coexists with inflammation-related tissue changes and a systemic inflammatory profile. Some years ago, we initiated our studies believing that the comprehension of host/parasite interplay contributing to CCC pathogenesis could unveil targets for rational trait-based modulatory therapies.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach*

Lannes‐Vieira

2022

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

Chagas disease (CD), caused by infection by the protozoan parasite Trypanosoma cruzi, presents as main clinical manifestation the chronic chagasic cardiomyopathy (CCC). CCC afflicts millions of people, mostly in Latin America, and vaccine and effective therapy are still lacking. Comprehension of the host/parasite interplay in the chronic phase of T. cruzi infection may unveil targets for rational trait-based therapies to improve CCC prognosis. In the present viewpoint, I critically summarise a collection of data, obtained by our network of collaborators and other groups on CCC and preclinical studies on pathogenesis, targeting identification for intervention and the use of drugs with immunomodulatory properties to improve CCC. In the last two decades, models combining mouse lineages and T. cruzi strains allowed replication of crucial clinical, histopathological, and immunological traits of CCC. This condition includes conduction changes (heart rate changes, arrhythmias, atrioventricular blocks, prolongation of the QRS complex and PR and corrected QT intervals), ventricular dysfunction and heart failure, CD8-enriched myocarditis, tissue remodeling and progressive fibrosis, and systemic inflammatory profile, resembling "cytokine storm". Studies on Chagas' heart disease pathogenesis begins to unveil the molecular mechanisms underpinning the inflammation-related cardiac tissue damage, placing IFNγ, TNF and NFκB signaling as upstream regulators of miRNAs and mRNAs associated with critical biological pathways as cell migration, inflammation, tissue remodeling and fibrosis, and mitochondrial dysfunction. Further, data on preclinical trials using hypothesis-based tools, targeting parasite and inflammationrelated alterations, opened paths for multi-therapeutic approaches in CCC. Despite the long path taken using experimental CD models replicating relevant aspects of CCC and testing new therapies and therapeutic schemes, these findings may get lost in translation, as conceptual and economical challenges, underpinning the valley of death across preclinical and clinical trials. It is hoped that such difficulties will be overcome in the near future.

show abstract

Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: Mechanisms and therapeutic implications

Middleton

McGregor

Webb

et al. 2022

Autoimmunity Reviews

View full text Add to dashboard Cite

Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies

Cited by 12 publications

References 63 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

Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach*

Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: Mechanisms and therapeutic implications

Contact Info

Product

Resources

About