Cytokine Networks as Targets for Preventing and Controlling Chagas Heart Disease

Abstract

Chagas disease, a neglected disease caused by the protozoan Trypanosoma cruzi, is endemic in 21 Latin American countries, affecting 6-8 million people. Increasing numbers of Chagas disease cases have also been reported in non-endemic countries due to migration, contamination via blood transfusions or organ transplantation, characterizing Chagas as an emerging disease in such regions. While most individuals in the chronic phase of Chagas disease remain in an asymptomatic clinical form named indeterminate, approximately 30% of the patients develop a cardiomyopathy that is amongst the deadliest cardiopathies known. The clinical distinctions between the indeterminate and the cardiac clinical forms are associated with different immune responses mediated by innate and adaptive cells. In this review, we present a collection of studies focusing on the human disease, discussing several aspects that demonstrate the association between chemokines, cytokines, and cytotoxic molecules with the distinct clinical outcomes of human infection with Trypanosoma cruzi. In addition, we discuss the role of gene polymorphisms in the transcriptional control of these immunoregulatory molecules. Finally, we discuss the potential application of cytokine expression and gene polymorphisms as markers of susceptibility to developing the severe form of Chagas disease, and as targets for disease control.

Keywords: Trypanosoma cruzi; chagas disease; cytokines; gene polymorphism; immunoregulation.

Figure 1

Schematic representation of cytokine expression in the indeterminate and cardiac clinical forms of Chagas disease. In the indeterminate clinical form, an increased expression of anti-inflammatory cytokines, such as IL-10 and IL-17 is observed. However, in the cardiac clinical form, the increased expression of pro-inflammatory cytokines, such as IFN-gamma and TNF, favor the establishment of the inflammatory environment. Cytokines, such as IL-7 and IL-15, have been associated with the cardiac clinical form.

Figure 2

Cytotoxic and inflammatory immune response in chronic Chagas cardiomyopathy. T cells mediate cytotoxicity in chronic Chagas cardiomyopathy. These cells are recruited to the heart by adhesion molecules and chemokines, and can release inflammatory cytokines and cytotoxic molecules, such as granzymes and perforins, that contribute to cardiac tissue damage, fibrosis, and disease severity (Designed with Biorender).

Figure 3

Cytokine activation of STAT and association with Th1/Th2 development. The engagement of inflammatory cytokines, such as IFN-gamma, IL6, IL12, and TNF, with their receptors favors the activation of transcription factors STAT1, STAT3, STAT4, and NF-kB, which contributes to the production of Th1 cytokines. While in modulatory environments, the presence of IL4 cytokine activates STAT6, which contributes to the production of Th2 cytokines. The association of STAT with cytokines (right corner of figure) emphasizes the main STAT associated with the cytokine, although other STAT may also be activated by the same cytokine (Designed with Biorender).