CCR5 Plays a Critical Role in the Development of Myocarditis and Host Protection in Mice Infected withTrypanosoma cruzi

Abstract

The pathogenesis of myocarditis during Trypanosoma cruzi infection is poorly understood. We investigated the role played by chemokine receptor 5 (CCR5) in the influx of T cells to the cardiac tissue of T. cruzi-infected mice. mRNA and protein for the CCR5 ligands CCL3, CCL4, and CCL5 were detected in the hearts of infected mice in association with CD4+ and CD8+ T cells. There was a high level of CCR5 expression on CD8+ T cells in the hearts of infected mice. Moreover, CCR5 expression on CD8+ T cells was positively modulated by T. cruzi infection. CCR5-deficient mice infected with T. cruzi experienced a dramatically inhibited migration of T cells to the heart and were also more susceptible to infection. These results suggest that CCR5 and its ligands play a central role in the control of T cell influx in T. cruzi-infected mice. Knowledge of the mechanisms that trigger and control the migration of cells to the heart in patients with Chagas disease may help in the design of drugs that prevent myocarditis and protect against the development of severe disease.

Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease

“…The chemokines CCL2/MCP-1 and CCL5-RANTES have been largely associated with leukocyte (monocytes and lymphocytes) recruitment to inflammatory foci to combat parasite infection, but this infiltration inevitably results in damage to the host tissues (Aliberti et al 1999, Talvani et al 2000, Teixeira et al 2002). In fact, the role of CCL5 in the recruitment of CCR5 + leukocytes has been reinforced by experiments that indicate that CCR5-deficient mice are more susceptible to T. cruzi infection after the reduction of macrophages and T-cell migration into the heart, especially during the early stages of infection (Machado et al 2005, Hardison et al 2006). Other evidence of this phenomenon is based on the partial blockage of the CC-chemokine receptor inhibitor (Met-RANTES), which induces a reduction in the leukocyte influx (modulated by T. cruzi), followed by a reduction in parasitaemia and a reduction in fibronectin deposition in the heart tissue (Marino et al 2004, Medeiros et al 2009).…”

Alloantigen-enhanced accumulation of CCR5+‘effector’ regulatory T cells in the gravid uterus

“…Proinflammatory effector T cells home to sites of infection outside the secondary lymph organs (21). In analogy one might expect a similar directed accumulation of CCR5 ϩ effector T R cells to the sites where their action is required.…”

“…Expression of CCR5 in pancreatic islets correlates with increased severity of diabetes in mice (19), and CCR5 is thought to mediate T cell migration to the islets (20). Deficiency in CCR5 leads to a reduced T cell infiltration to sites of Trypanosoma cruzei (21), Toxoplasma gondii (22), and viral infections (23). CCR5 also mediates infiltration of allografts (24)(25)(26)(27) by proinflammatory, IFN␥-producing T helper (T H ) 1-biased cells (17,26) and macrophage infiltration at sites of inflammation (28,29).…”

Chagas' disease and Duffy antigen/receptor for chemokine (DARC): a mini-review

“…Polymorphism in the promoter region of the CCR5 gene (CCR5 59029 A→G), associated with lower CCR5 expression in leukocytes was more frequent in asymptomatic patients than those with chagasic cardiomyopathy (78,81). Others studies have shown that mice lacking the CCR5 receptor present a significant reduction of cardiac inflammatory infiltrate, suggesting the importance of this receptor in lymphocyte migration and control of local parasite replication (82). It is important to emphasize that DARC presents a significant homology with receptor CCR5, and it is also a receptor for chemokine CCL5 (55).…”