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

Abstract

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.

Cytokine profile levels and their relationship with parasitemia and cardiomyopathy in people with Chagas disease in Spain. A prospective observational study

“…Moreover, there are several studies that show that transforming growth factor beta (TGF-β) modulates the host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. Pre-clinical studies have shown that TGF-β signaling inhibitors may revert these effects, opening the door to a promising therapeutic approach (Ferreira et al 2022 ).…”

State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

“… 150 , 151 TGF-β plays a key role in proliferation and differentiation of tissues, as well as in the remodeling of their extracellular matrix. 152 It has also been described to be involved in preventing the development of uncontrolled, potentially life-threatening, inflammatory responses during the acute phases of infection. 19 TGF-β polymorphisms have been associated with increased risk of developing CCC and its expression is greatly increased in the early and chronic stages of T. cruzi infection.…”

Novel roles of PIWI proteins and PIWI-interacting RNAs in human health and diseases

“…T.cruzi , which can penetrate the interstitial vascular system and eventually invade cardiomyocytes, causes heart disease and results in myocardial damage and conduction abnormalities [ 261 , 357 ]. T. cruzi has a highly differential expression of the fibrosis gene, such as metalloproteinase families MMP2, MMP9 and MMP12, as well as abnormal expression of TGF-β, which ultimately causes cardiac fibroblasts to differentiate into myofibroblasts [ 358 – 360 ]. The expression of some novel piRNAs is significantly induced at the early stage of the infection.…”