Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole-blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8+ T-cell cytotoxicity, separated the 2 groups. NK/CD8+ T-cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression.

Hydroxymethylnitrofurazone treatment in indeterminate form of chronic Chagas disease: Reduced intensity of tissue parasitism and inflammation—A histopathological study

“…Histopathological analysis of hearts from patients with chronic Chagas cardiomyopathy reveals a diffuse infiltrating inflammatory, hypertrophy, fibrosis and myocarditis with scarce tissue parasitism. [71][72][73] In the previous literature, the immunosuppression during the chronic phase of Chagas disease (Y strain) caused development of myocardial lesions in mice. 69 In our study, 100% of the infected animals were found to have cardiac hypertrophy and inflammatory infiltrates that were statistically different from the NEG group.…”

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

“…In the context of human infection, Ferreira et al (68) conducted a microarray-based transcriptomic signature study on peripheral blood cells from Chagas disease patients, in which ex vivo transcriptional profiles were compared between patients classified in different categories: severe cardiopathy, mild cardiopathy, asymptomatic with negative PCR for T. cruzi DNA, asymptomatic with positive PCR, and control non-infected subjects. The expression of genes related to NK cells activity was found to be upregulated in positive PCR asymptomatic patients and mild cardiopathy patients, and downregulated in patients with severe cardiopathy (68).…”

“…The expression of genes related to NK cells activity was found to be upregulated in positive PCR asymptomatic patients and mild cardiopathy patients, and downregulated in patients with severe cardiopathy (68). …”

PARP1-cGAS-NF-κB pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and Chagas disease

“…Seropositive individuals are categorized as indeterminate (C0) when they exhibit no symptoms of heart involvement, and progress through C1-C3 stages of clinical Chagas disease presented with increasing severity of structural and functional alterations in the heart [22,23]. While the indeterminate clinical form is biased towards an anti-inflammatory profile, the C1-C3 CD patients routinely present proinflammatory profile [6,[28][29][30] [6,[24][25][26] associated with a systemic increase in TNF-α + monocytes [27][28][29], oxidative stress (e.g. lipid hydroperoxides) [30,31], and an abundance of CD8 + T cells that express inflammatory cytokines and cytotoxic molecules [32].…”