The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection withTrypanosoma cruzi

Abstract

Infection of susceptible mice with the Colombiana strain of Trypanosoma cruzi results in an orchestrated expression of chemokines and chemokine receptors within the heart that coincides with parasite burden and cellular infiltration. CC chemokine receptor 5 (CCR5) is prominently expressed during both acute and chronic disease, suggesting a role in regulating leukocyte trafficking and accumulation within the heart following T. cruzi infection. To better understand the functional role of CCR5 and its ligands with regard to both host defense and/or disease, CCR5؊/؊ mice were infected with T. cruzi, and the disease severity was evaluated. Infected CCR5؊/؊ mice develop significantly higher levels of parasitemia (P < 0.05) and cardiac parasitism (P < 0.01) during acute infection that correlated with reduced survival. Further, we show that CCR5 is essential for directing the migration of macrophages and T cells to the heart early in acute infection with T. cruzi. In addition, data are provided demonstrating that CCR5 does not play an essential role in maintaining inflammation in the heart during chronic infection. Collectively, these studies clearly demonstrate that CCR5 contributes to the control of parasite replication and the development of a protective immune response during acute infection but does not ultimately participate in maintaining a chronic inflammatory response within the heart.

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

“…Knockdown of CCL5 secretion by tumors reduced the migration of CD103 + Tregs into tumors. CCL5 and its receptor CCR5 have been identified as mediators of acute and chronic inflammation by mediating the migration of leukocytes into inflamed tissues (24)(25)(26). Thus, our findings further provide a linkage among inflammation, tumor, and tissue-homing effector/memory Tregs.…”

TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

“…Treatment with Met-RANTES, a partial CCR1/CCR5 antagonist, decreases cell infiltration in T. cruzi-infected murine hearts and has a beneficial effect on survival ). In addition, infected CCR5 -/-mice have deficient recruitment of T cells and macrophages to the heart (Hardison et al 2006). These findings implicate CCR5 in the active development of T. cruzi-elicited myocarditis.…”

“…In the present study, we demonstrated that interfering with the biological effects of TNF-α using Infliximab, an antibody that blocks soluble and membrane-bound TNF-α (Wong et al 2008), led to CCR5 down-modulation and ameliorated heart inflammation without interfering with parasite control. On the other hand, infection of CCR5 -/-mice results in higher parasite burden, mortality, and impaired macrophage and T cell influx into the cardiac tissue (Hardison et al 2006). Therefore, we believe that the total absence of either TNFR1 or CCR5 signaling impairs the entrance of parasite-controlling cells in the heart, while the partial reduction of TNF-α and CCR5 signaling promotes beneficial effects for cardiomyopathy.…”

“…Since CCR5 is required to recruit T cells into cardiac tissue during T. cruzi infection , Hardison et al 2006) and TNFR1 -/-mice had defective cardiac infiltration and splenic retention of CD8 + cells, we studied the frequency of CD8 + CCR5 + cells available for tissular recruitment in infected TNFR1 -/-mice. During T. cruzi infection, an increased frequency of CD8 + CCR5 + cells was detected in the blood (Fig.…”

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).…”