IL-17 Produced during Trypanosoma cruzi Infection Plays a Central Role in Regulating Parasite-Induced Myocarditis

Abstract

BackgroundChagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi. Around 30% of the infected patients develop chronic cardiomyopathy or megasyndromes, which are high-cost morbid conditions. Immune response against myocardial self-antigens and exacerbated Th1 cytokine production has been associated with the pathogenesis of the disease. As IL-17 is involved in the pathogenesis of several autoimmune, inflammatory and infectious diseases, we investigated its role during the infection with T. cruzi.Methodology/Principal FindingsFirst, we detected significant amounts of CD4, CD8 and NK cells producing IL-17 after incubating live parasites with spleen cells from normal BALB/c mice. IL-17 is also produced in vivo by CD4+, CD8+ and NK cells from BALB/c mice on the early acute phase of infection. Treatment of infected mice with anti-mouse IL-17 mAb resulted in increased myocarditis, premature mortality, and decreased parasite load in the heart. IL-17 neutralization resulted in increased production of IL-12, IFN-γ and TNF-α and enhanced specific type 1 chemokine and chemokine receptors expression. Moreover, the results showed that IL-17 regulates T-bet, RORγt and STAT-3 expression in the heart, showing that IL-17 controls the differentiation of Th1 cells in infected mice.Conclusion/SignificanceThese results show that IL-17 controls the resistance to T. cruzi infection in mice regulating the Th1 cells differentiation, cytokine and chemokine production and control parasite-induced myocarditis, regulating the influx of inflammatory cells to the heart tissue. Correlations between the levels of IL-17, the extent of myocardial destruction, and the evolution of cardiac disease could identify a clinical marker of disease progression and may help in the design of alternative therapies for the control of chronic morbidity of chagasic patients.

Immunoregulatory networks in human Chagas disease

“…In an attempt to study the role of IL-17 in protection, a series of experiments were performed using IL-17A knock out mice, as well as anti-IL-17 treatment. Results showed that while increased IL-17 expression was associated with susceptibility to T. cruzi infection in a murine model using bradykinin receptor 2−/− mice (52), other studies have shown that mice treated with anti-IL-17 and IL-17−/− mice exhibited earlier mortality as compared to controls, and that inhibition of IL-17 also resulted in greater heart inflammation (51, 53). Studies of IL-17 expression in Chagas patients showed that indeterminate patients display a higher frequency of IL-17+ T cells as compared to cardiac patients (50).…”

Developments in the management of Chagas cardiomyopathy

“…[23,24] Activation of CD4 + and CD8 + T cells that synthesize Th1 cytokines generally correlates with myocardial damage, at least in experimental models, and may be modulated by IL-17 and T regulatory cells. [21,25,26] During acute infection, mononuclear cells produce high levels of IFN-γ,[27] TNF-α and IL-6. [28]…”

Foxp3+CD25high CD4+ regulatory T cells from indeterminate patients with Chagas disease can suppress the effector cells and cytokines and reveal altered correlations with disease severity

“…Recently it has been described that IL-17 plays a role in controlling the resistance of experimental T. cruzi infection by modulating the Th1 response, therefore regulating the extent of myocardial destruction induced by the parasite (Guedes et al 2010). Regarding that Treg cells of IND group are prompt to produce high levels of IL-17 and IL-10 is possible to speculate that this cell-type might contribute to modulate the inflammatory response during the asymptomatic infection.…”