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.

TNF blockers alone and associated with Benznidazole impact in vitro cytokine dynamics in chronic Chagas disease

“…While there is a predominance of anti-inflammatory cytokines in the IND form, cardiac impairment is evidenced by greater production of pro-inflammatory cytokines, especially TNF. [14][15][16][17][18][19][20][21][22][23] Initially, we evaluated cytokine production among carriers only in the culture condition with only PBMCs. Our data indicate an increase in TNF in patients with severe Chagas heart disease (CARD2) compared to those with mild Chagas heart disease (CARD1) and NEG.…”

“…This demonstrates that it is the infectious agent, T. cruzi, that triggers the levels of these cytokines since the IDIOP group of individuals is clinically similar to the CARD2 group, which suggests that patients with Chagas heart disease have cardiac tissue damage induced by a breakdown of immunological homeostasis and consequently loss of immunoregulatory mechanisms induced by the presence of the parasite in this tissue. 10,14,15 Chronic Chagas heart disease has been related to a dysregulation between Th1 and Th2 cells, where there is a predominance of cytokine production of the pro-inflammatory profile, especially TNF and IFN-γ, by TCD4+ lymphocytes. TCD8+ and CD14+ monocytes and cardiac tissue characterise the intense inflammation and Th1 response.…”

“…26 idiopathic heart disease and healthy individuals within 48 h. Understanding the profile of these cytokines in Chagas disease can serve as immunotherapeutic targets in addition to biomarkers for preventing progression and control in chronic disease. 14 TNF inhibitors are among the most successful drugs in the treatment of chronic inflammatory and autoimmune diseases such as arthritis, especially rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel diseases, in addition to many case studies involving these biologics and parasitic diseases, such as Leishmaniasis. 24,28 The effects of these immunomodulatory drugs on the course of Chagas disease in humans are unknown.…”

“…[10][11][12][13] Cytokines produced by lymphocytes regulate the immune response and are implicated in resistance to infection and the clinical evolution of patients with Chagas disease. 10,14 Analysis of pro-and anti-inflammatory cytokine profiles suggest that IL-10 is higher in individuals with the indeterminate form when compared to those with the cardiac form. On the other hand, pro-inflammatory cytokines, such as interferon-gamma (IFN-γ) and tumour necrosis factor (TNF), are at higher levels in patients with the cardiac form and possibly represent a worsening of cardiac function.…”

“…On the other hand, pro-inflammatory cytokines, such as interferon-gamma (IFN-γ) and tumour necrosis factor (TNF), are at higher levels in patients with the cardiac form and possibly represent a worsening of cardiac function. [14][15][16][17][18][19] TNF is the most explored of all cytokines, although some studies bring its somewhat controversial role between the increase in chronic carriers and low or undetectable levels in others. This cytokine binds to its receptors, TNFR1 and TNFR2, which also participate in immunopathology associated with cardiac damage or regulation.…”