Abstract
Chronic cardiomyopathy is the main clinical manifestation of Chagas disease (CD), a disease caused by Trypanosoma cruzi infection. A hallmark of chronic chagasic cardiomyopathy (CCC) is a fibrogenic inflammation mainly composed of CD8+ and CD4+ T cells and macrophages. CC-chemokine ligands and receptors have been proposed to drive cell migration toward the heart tissue of CD patients. Single nucleotide polymorphisms (SNPs) in CC-chemokine ligand and receptor genes may determine protein expression. Herein, we evaluated the association of SNPs in the CC-chemokines CCL2 (rs1024611) and CCL5 (rs2107538, rs2280788) and the CCL5/RANTES receptors CCR1 (rs3181077, rs1491961, rs3136672) and CCR5 (rs1799987) with risk and progression toward CCC. We performed a cross-sectional association study of 406 seropositive patients from endemic areas for CD in the State of Pernambuco, Northeast Brazil. The patients were classified as non-cardiopathic (A, n = 110) or cardiopathic (mild, B1, n = 163; severe, C, n = 133). Serum levels of CCL5 and CCL2/MCP-1 were elevated in CD patients but were neither associated with risk/severity of CCC nor with SNP genotypes. After logistic regression analysis with adjustment for the covariates gender and ethnicity, CCL5 −403 (rs2107538) CT heterozygotes (OR = 0.5, P-value = 0.04) and T carriers (OR = 0.5, P-value = 0.01) were associated with protection against CCC. To gain insight into the participation of the CCL5–CCR5/CCR1 axis in CCC, mice were infected with the Colombian T. cruzi strain. Increased CCL5 concentrations were detected in cardiac tissue. In spleen, frequencies of CCR1+ CD8+ T cells and CD14+ macrophages were decreased, while frequencies of CCR5+ cells were increased. Importantly, CCR1+CD14+ macrophages were mainly IL-10+, while CCR5+ cells were mostly TNF+. CCR5-deficient infected mice presented reduced TNF concentrations and injury in heart tissue. Selective blockade of CCR1 (Met-RANTES therapy) in infected Ccr5−/− mice supported a protective role for CCR1 in CCC. Furthermore, parasite antigen stimulation of CD patient blood cells increased the frequency of CCR1+CD8+ T cells and CCL5 production. Collectively, our data support that a genetic variant of CCL5 and CCR1+ cells confer protection against Chagas heart disease, identifying the CCL5-CCR1 axis as a target for immunostimulation.
Highlights
Chagas disease (CD) is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi
To gain insight into the contribution of CCL5 and its receptors CCR1 and CCR5 to the pathogenesis of Chagas heart disease, we used an experimental model of chagasic cardiomyopathy (CCC) [27, 28], CCR5-deficient mice and interventions with the CCR1/ CCR5 antagonist Met-RANTES
In this group of patients, CCL5 −403C > T CT heterozygotes and T carriers were associated with protection against heart disease, whereas other variants at the CCL2, CCL5, CCR1, and CCR5 genes were not associated with the outcome of Chagas heart disease in this population
Summary
Chagas disease (CD) is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. 1 to 2 million CD patients are living in the USA, Europe, and Asia, where parasite transmission poses a risk through organ transplantation, blood transfusion, and pregnancy [2]. The intensity of fibrogenic heart inflammation, mainly composed of CD8+ and CD4+ T-cells and macrophages, is linked to CCC severity [4, 5]. In accordance with this differential accumulation of mononuclear cells, CC-chemokines and their receptors have been proposed to play a crucial role in the recruitment and migration of circulating cells toward the heart tissue in chronic CD, both in humans and experimental models [6]. In non-chagasic heart diseases, innate and adaptive immune cells, spleen-born T cells and macrophages, are involved in both heart tissue injury and repair [7, 8]
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