Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy

Frade-Barros, Amanda Farage; Ianni, Bárbara Maria; Cabantous, Stéphanie; Pissetti, Cristina Wide; Saba, Bruno; Lin-Wang, Hui Tzu; Buck, Paula; Marin-Neto, José Antônio; Schmidt, André; Dias, Fabrício C.; Hirata, Mário Hiroyuki; Sampaio, Marcelo Ferraz; Fragata, Abílio; Pereira, Alexandre C.; Donadi, Eduardo Antônio; Rodrigues, Virmondés; Kalil, Jorge; Chevillard, Christophe; Cunha‐Neto, Edécio

doi:10.3389/fimmu.2020.01386

Cited by 18 publications

(11 citation statements)

References 40 publications

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“…The pathogenesis of CCC is still to be completely understood ( 6 ). Low-grade chronic T. cruzi persistence, which drives continued production of IFN-γ and TNF-α by Th1 T cells immune cells, plays a central pathogenic role in CCC ( 2 , 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

et al. 2021

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Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes’ mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

et al. 2021

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“…In addition, it is postulated that the genetic factors of the patient are related to the diversity in the clinical course of CD 11 . Biomarkers for CHD progression are being studied in the immunological and molecular fields, in which enzymatic, humoral, and immunological interactions may be related to a set of genetic markers (polymorphisms) already existing, when the patient is infected, and these different responses to the parasite may determine disease progression 12 .…”

Section: Introductionmentioning

confidence: 99%

Indeterminate form of Chagas disease: historical, conceptual, clinical, and prognostic aspects

Hasslocher‐Moreno

Xavier

Saraiva

et al. 2021

Rev. Soc. Bras. Med. Trop.

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Chagas disease (CD) remains a serious endemic disease in Latin America and a major public health problem. Because of globalization, the disease has spread to non-endemic areas in the northern hemisphere. In the chronic phase of the disease, most patients present with the indeterminate form (IF), characterized by positive serology for Trypanosoma cruzi, absence of clinical findings, and normal findings in electrocardiogram (ECG). IF was not recognized as a clinical entity until decades after the discovery of the disease, and only in the 1940-50s, it was categorized as a form of CD, and its conceptual definition was ratified in the 1980s. Children, adolescents, and young adults with the IF benefit from etiological treatment and tend to have less progression to heart disease in the long term than the untreated ones. IF patients have an essentially benign clinical condition, and their prognosis can be compared to that of healthy individuals with normal ECG findings. Currently, because of aging, patients with the IF have comorbidities that require attention in health services.

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“…[ 105 ]. In Brazil, the variants IL17A and IL17F are associated with the development of cardiomyopathy [ 106 ] In the African/African-American population, p.Arg514-Gly, a polymorphism of ACE2, is associated with cardiovascular and pulmonary conditions [ 107 ] In Genome-wide Association Study (GWAS) in Italian and Spanish hospitals, a 3p21.31 gene cluster encompassed the SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1 genes [ 108 ] Genetic polymorphisms of Interferon-γ Production In the Brazilian population, genotypes and alleles of IL12B and IL-10 could be associated with a failure to regulate Th1 responses, IFNγ production, and an increased risk of chronic CD cardiomyopathy [ 109 ] Interferon-gamma gene (IFNG) + 874 T/A polymorphism could be related to a predisposition to CD in the South American population [ 110 ] The single nucleotide polymorphism (SNP) rs6598045 of the interferon-induced transmembrane protein 3 (IFITM3) gene correlates with COVID-19 fatality rates [ 111 ] Populations with a low allele frequency of rs1990760 (T allele) in IFIH1 (InterFeron-Induced Helicase 1; MDA5) are associated with less IFN-beta expression and potential susceptibility to COVID-19 infection [ 112 ] ABO blood group system Inconclusive studies found an increase in blood group B patients dying suddenly from CD [ 113 ] The histo-blood group system explored by GTA, GTB, FUT II, and FUT III glycosyltransferases found that B plus AB secretor phenotypes are related to megaesophagus and megacolon in CD [ 114 ] GWAS found blood group A is associated with COVID-19 and respiratory failure [ 111 ] Type A blood is associated with the risk of in-hospital death [ 115 ] Ethnicity CD with megacolon, calibre and length of the rectosigmoid depends on altitude, ethnicity, and diet [ 116 ] COVID-19 presents an increased risk depending on the population studied, e.g. Black and Asian compared to white subjects had increased risk infection of COVID-19 [ 117 ] In Mexico, native peoples have a higher risk of death due to COVID-19 [ 118 ] Dysregulated immunothrombosis Hypercoagulability The activation of haemostasis is related to the activation and increase of various molecules, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…In the Brazilian population, genotypes and alleles of IL12B and IL-10 could be associated with a failure to regulate Th1 responses, IFNγ production, and an increased risk of chronic CD cardiomyopathy [ 109 ]…”

Section: Introductionmentioning

confidence: 99%

Immunothrombotic dysregulation in chagas disease and COVID-19: a comparative study of anticoagulation

et al. 2021

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Chagas and COVID-19 are diseases caused by Trypanosoma cruzi and SARS-CoV-2, respectively. These diseases present very different etiological agents despite showing similarities such as susceptibility/risk factors, pathogen-associated molecular patterns (PAMPs), recognition of glycosaminoglycans, inflammation, vascular leakage hypercoagulability, microthrombosis, and endotheliopathy; all of which suggest, in part, treatments with similar principles. Here, both diseases are compared, focusing mainly on the characteristics related to dysregulated immunothrombosis. Given the in-depth investigation of molecules and mechanisms related to microthrombosis in COVID-19, it is necessary to reconsider a prompt treatment of Chagas disease with oral anticoagulants.

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Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy

Cited by 18 publications

References 40 publications

Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

Indeterminate form of Chagas disease: historical, conceptual, clinical, and prognostic aspects

Immunothrombotic dysregulation in chagas disease and COVID-19: a comparative study of anticoagulation

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