Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) Antagonist (Met-RANTES) Controls the Early Phase of Trypanosoma cruzi –Elicited Myocarditis

Abstract

Background-Comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate strategies aimed at ameliorating the inflammation associated with heart dysfunction. The augmented expression of CC chemokines, especially CCL5/RANTES and CCL3/MIP-1␣, in the hearts of infected mice suggests a role for CC chemokines and their receptors in the pathogenesis of T cruzi-elicited myocarditis. Methods and Results-We report that during the early phase of infection in C3H/HeJ mice infected with 100 blood trypomastigotes of T cruzi, most of the inflammatory cells invading the heart tissue were CD8 ϩ cells and expressed CCR5, a CCL5/RANTES, and CCL3/MIP1-␣ receptor. Furthermore, peripheral blood CD8 ϩ T lymphocytes displayed increased expression of CCR5. These findings led us to use Met-RANTES, a selective CCR1 and CCR5 antagonist, to modulate the acute T cruzi-elicited myocarditis. Met-RANTES treatment did not interfere with parasitism but significantly decreased the numbers of CD4 ϩ and CD8 ϩ T cells, CCR5 ϩ , and interleukin-4 ϩ cells invading the heart, paralleling the diminished deposition of fibronectin. Moreover, Met-RANTES treatment resulted in increased survival of infected animals, compared with saline treatment. Conclusions-These results indicate that the massive influx of CCR5ϩ cells into cardiac tissue is not crucial for cell-mediated anti-T cruzi immunity but appears to be critical for pathogenesis of T cruzi-elicited myocarditis. Thus, CC chemokine receptors might become an attractive therapeutic target for further evaluation during T cruzi infection.

CC-chemokine receptors: a potential therapeutic target for Trypanosoma cruzi-elicited myocarditis

“…Further, increased levels of CCL5/RANTES, CCL3/MIP-1α, CCL4/ MIP-1β, CCL2/MCP-1 and the CXC chemokines CXCL10/ IP-10 and CXCL9/MIG mRNA have been detected in the heart tissue of acutely and chronically T. cruzi-infected mice (Talvani et al 2000, Aliberti et al 2001, dos Santos et al 2001, Marino et al 2004, implicating a potential role for these molecules in Chagas disease.…”

“…To shed light on this question, we analyzed the production of these chemokines in the early phase of the infection. In fact, CCL2, CCL3, CCL5, and, in lesser extend, CCL4 are enhanced as early as 28 days pot-infection, paralleling the leukocyte influx, mainly composed of CD8 + T cells, into the cardiac tissue (Marino et al 2004). Most of these inflammatory cells infiltrating the cardiac tissue of infected mice are CCR5-bearing mononuclear cells.…”

“…Thus, the lower frequency of CCR5 + peripheral blood leukocytes in chagasic individuals with more severe disease can be due to the presence of heart dysfunction. Moreover, it has been reported that T cells present in the heart of T. cruziinfected mice, mostly CD8 + , express CCR5 (Teixeira et al 2002, Marino et al 2004). Altogether, these data favor a relevant pathophysiological role for CCR5 and its ligands in T. cruzi-triggered myocarditis.…”

“…Trying to understand the molecular mechanisms involved in T. cruzi-elicited myocarditis with prevalence of CD8 + T cells, we have investigated the expression of inflammatory CC-chemokines in the heart of Colombiana straininfected C3H/He mice. Interestingly, increased expression of CCL2, CCL3, CCL4 and CCL5 was observed during the acute and chronic phases (dos Santos et al 2001, Marino et al 2004). These CC-chemokines are described to attract activated leukocytes, preferentially CD8 + T cells (Sallusto 1998, Cook et al 1999.…”

Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy

“…This inflammatory T cell and antibody response leads to control -but not complete elimination -of tissue and blood parasitism. On the other hand, the blockade of CCR5 with Met-RANTES significantly decreased the intensity of cardiac inflammatory infiltrate, suggesting that lymphocyte migration to the myocardium during acute infection is dependent on CCR5 ligands (Marino et al 2004). The Syrian hamster model of T. cruzi infection reproduces the range of different outcomes of human Chagas disease (Ramirez et al 1994, Bilate et al 2003.…”