Study of the Activity of 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one against Schistosomiasis Mansoni in Mice

Previous studies conducted with the imidazolidinic derivative 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one (LPSF-PT05) show outstanding activity against adult Schistosoma mansoni worms in vitro. In the first phase of this study, S. mansoni-infected mice were treated, orally, with 100 mg/Kg of the LPSF-PT05 in three formulations: Tween 80 and saline solution, oil/water (70 : 30) emulsion, and solid dispersion with polyethylene glycol (PEG). In the second phase, three other doses of the LPSF-PT05 in PEG were tested: 3, 10, 30 mg/kg. These treatment regimens significantly reduced the number of recovered worms due to increases in the solubility of the compound in this formulation; the greatest reduction (70.5%) was observed at the dose of 100 mg/kg. There was no changes in the pattern of mature egg compared to immature eggs; however there was a significant increase in the number of dead eggs. Histopathological analysis of liver tissue showed changes in morphological aspects of the hepatic parenchyma with decrease exudative-productive hepatic granuloma stages, although we found no significant differences in IFN-γ, IL-4, IL-10, or NO production in response to the specific antigen SEA. The results show the derivative LPSF-PT05 to be a potential candidate in the etiological treatment of schistosomiasis with a possible dampening effect of the granulomatous process

Genetic Polymorphism at CCL5 Is Associated With Protection in Chagas’ Heart Disease: Antagonistic Participation of CCR1+ and CCR5+ Cells in Chronic Chagasic Cardiomyopathy

Submitted by Sandra Infurna ([email protected]) on 2018-04-12T11:07:45Z No. of bitstreams: 1 joselilannes2_vieira_etal_IOC_2018.pdf: 2737835 bytes, checksum: 5a14821aaf12a2de79b739e8b2806eea (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-04-12T11:27:34Z (GMT) No. of bitstreams: 1 joselilannes2_vieira_etal_IOC_2018.pdf: 2737835 bytes, checksum: 5a14821aaf12a2de79b739e8b2806eea (MD5)Made available in DSpace on 2018-04-12T11:27:35Z (GMT). No. of bitstreams: 1 joselilannes2_vieira_etal_IOC_2018.pdf: 2737835 bytes, checksum: 5a14821aaf12a2de79b739e8b2806eea (MD5) Previous issue date: 2018Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Ambulatório de Doença de Chagas e Insuficiência Cardíaca do Pronto Socorro Cardiológico de Pernambuco. Recife, PE, Brasil.Ambulatório de Doença de Chagas e Insuficiência Cardíaca do Pronto Socorro Cardiológico de Pernambuco. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil.Universidade Federal Fluminense. Faculdade de Medicina. Departamento de Patologia. Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Laboratório de Imunoparasitologia. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Laboratório de Imunoparasitologia. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Laboratório de Imunoparasitologia. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Laboratório de Imunoparasitologia. Recife, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Medicina Tropical. Recife, PE, Brasil / Universidade Federal de Pernambuco. Laboratório de Imunopatologia Keizo Asami. Recife, PE, Brasil.Universidade Federal do Rio de Janeiro. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica. Rio de Janeiro, RJ, Brasil.Ambulatório de Doença de Chagas e Insuficiência Cardíaca do Pronto Socorro Cardiológico de Pernambuco. Recife, PE, Brasil.Ambulatório de Doença de Chagas e Insuficiência Cardíaca do Pronto Socorro Cardiológico de Pernambuco. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ. Brasil.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

Image_8.tif

<p>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.</p

Data_Sheet_1.docx

<p>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.</p

Image_6.tif

<p>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.</p

Image_3.tif

<p>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.</p

Image_9.tif

<p>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.</p

Image_7.tif

<p>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.</p

Image_1.tif

<p>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.</p