TGF-<i>β</i> Polymorphisms Are a Risk Factor for Chagas Disease

Ferreira, Roberto Rodrigues; Madeira, Fabiana da Silva; Alves, Gabriel Farias; Chambela, Mayara da Costa; Curvo, Eduardo de Oliveira Vaz; Moreira, Aline dos Santos; Sá, Renata Almeida de; Mendonça-Lima, Leila; Cabello, Pedro Hernán; Bailly, Sabine; Feige, Jean‐Jacques; Araújo-Jorge, Tânia C.; Saraiva, Roberto Magalhães; Waghabi, Mariana Caldas

doi:10.1155/2018/4579198

Cited by 9 publications

(8 citation statements)

References 48 publications

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“…Particularly, genes encoding cytokines/chemokines involved in inflammatory and immune response have been proposed as biomarkers (Calzada et al, 2009; Torres et al, 2010; Pissetti et al, 2011; Flórez et al, 2012; Nogueira et al, 2015; Furini et al, 2016; Ferreira et al, 2018). Thus, TGF-β1 polymorphism, mainly CT and TT genotypes at position – 509 of the TGFB1 gene have been associated with the susceptibility of acquiring CD in a Brazilian population (Ferreira et al, 2018). The same genotype, in addition to the genotypes −988 C/A; −800 G/A; −10 T/C; and 263 C/T has been studied in the Colombian and Peruvian populations.…”

Section: Family Clustering Of Congenital Transmission Of T Cruzi Infmentioning

confidence: 99%

Congenital Transmission of Trypanosoma cruzi: A Review About the Interactions Between the Parasite, the Placenta, the Maternal and the Fetal/Neonatal Immune Responses

et al. 2019

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Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi , is considered a neglected tropical disease by the World Health Organization. Congenital transmission of CD is an increasingly relevant public health problem. It progressively becomes the main transmission route over others and can occur in both endemic and non-endemic countries. Though most congenitally infected newborns are asymptomatic at birth, they display higher frequencies of prematurity, low birth weight, and lower Apgar scores compared to uninfected ones, and some suffer from severe symptoms. If not diagnosed and treated, infected newborns are at risk of developing disabling and life-threatening chronic pathologies later in life. The success or failure of congenital transmission depends on interactions between the parasite, the placenta, the mother, and the fetus. We review and discuss here the current knowledge about these parameters, including parasite virulence factors such as exovesicles, placental tropism, potential placental defense mechanisms, the placental transcriptome of infected women, gene polymorphism, and the maternal and fetal/neonatal immune responses, that might modulate the risk of T. cruzi congenital transmission.

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Section: Family Clustering Of Congenital Transmission Of T Cruzi Infmentioning

confidence: 99%

Congenital Transmission of Trypanosoma cruzi: A Review About the Interactions Between the Parasite, the Placenta, the Maternal and the Fetal/Neonatal Immune Responses

et al. 2019

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“…Chagas disease patients presenting more severe forms of heart disease progression have higher levels of circulating TGF-β [8, 11]. Single nucleotide polymorphisms in the TGF-β gene (-509 C<T and +10 T<C) were shown to be a risk factor for CD susceptibility, at least in the Latin American population [13,14]. Moreover, chronic chagasic patients with higher TGF-β levels present a worse clinical outcome after 10 years of follow up [15].…”

Section: Introductionmentioning

confidence: 99%

TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas’ heart disease

et al. 2019

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TGF-β involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-β signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TβR1/ALK5, on cardiac function in an experimental model of chronic Chagas’ heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (10 2 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-β signaling pathway reduced TGF-β/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3 + cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas’ heart disease by TGF-β inhibitors.

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“…We also correlated the expression of different TGF-b1 alleles with the susceptibility of CD development. We demonstrated that two TGF-b1 polymorphisms, -509 C>T (rs1800469) and codon 10 T>C (rs1800470), are associated with the susceptibility to the development of the disease in Brazilian cohort (Ferreira et al, 2018). Thus, TGF-b1 is a potential serological marker with predictive value in the clinic for patients in the early stages of the disease.…”

Section: Tgf-b and Chagas Diseasementioning

confidence: 91%

The Search for Biomarkers and Treatments in Chagas Disease: Insights From TGF-Beta Studies and Immunogenetics

Ferreira

Waghabi

Bailly

et al. 2022

Front. Cell. Infect. Microbiol.

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The anti-inflammatory cytokine transforming growth factor beta (TGF-β) plays an important role in Chagas disease (CD), a potentially life-threatening illness caused by Trypanosoma cruzi. In this review we revisited clinical studies in CD patients combined with in vitro and in vivo experiments, presenting three main sections: an overview of epidemiological, economic, and clinical aspects of CD and the need for new biomarkers and treatment; a brief panorama of TGF-β roles and its intracellular signaling pathways, and an update of what is known about TGF-β and Chagas disease. In in vitro assays, TGF-β increases during T. cruzi infection and modulates heart cells invasion by the parasite fostering its intracellular parasite cycle. TGF-β modulates host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. TGF-β signaling inhibitors reverts these effects opening a promising therapeutic approach in pre-clinical studies. CD patients with higher TGF-β1 serum level show a worse clinical outcome, implicating a predictive value of serum TGF-β as a surrogate biomarker of clinical relevance. Moreover, pre-clinical studies in chronic T. cruzi infected mice proved that inhibition of TGF-β pathway improved several cardiac electric parameters, reversed the loss of connexin-43 enriched intercellular plaques, reduced fibrosis of the cardiac tissue, restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Finally, TGF-β polymorphisms indicate that CD immunogenetics is at the base of this phenomenon. We searched in a Brazilian population five single-nucleotide polymorphisms (-800 G>A rs1800468, -509 C>T rs1800469, +10 T>C rs1800470, +25 G>C rs1800471, and +263 C>T rs1800472), showing that CD patients frequently express the TGF-β1 gene genotypes CT and TT at position -509, as compared to noninfected persons; similar results were observed with genotypes TC and CC at codon +10 of the TGF-β1 gene, leading to the conclusion that 509 C>T and +10 T>C TGF-β1 polymorphisms are associated with Chagas disease susceptibility. Studies in genetically different populations susceptible to CD will help to gather new insights and encourage the use of TGF-β as a CD biomarker.

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TGF-β Polymorphisms Are a Risk Factor for Chagas Disease

Cited by 9 publications

References 48 publications

Congenital Transmission of Trypanosoma cruzi: A Review About the Interactions Between the Parasite, the Placenta, the Maternal and the Fetal/Neonatal Immune Responses

Congenital Transmission of Trypanosoma cruzi: A Review About the Interactions Between the Parasite, the Placenta, the Maternal and the Fetal/Neonatal Immune Responses

TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas’ heart disease

The Search for Biomarkers and Treatments in Chagas Disease: Insights From TGF-Beta Studies and Immunogenetics

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