Expression and production of cardiac angiogenic mediators depend on the Trypanosoma cruzi-genetic population in experimental C57BL/6 mice infection

Shrestha, Deena; Bajracharya, Bijay; Paula-Costa, Guilherme; Salles, Beatriz C.S.; Leite, Ana; Menezes, Ana Paula de Jesus; Souza, Débora Ms; Oliveira, Laser Antônio Machado; Talvani, André

doi:10.1016/j.mvr.2016.12.002

Cited by 11 publications

(4 citation statements)

References 55 publications

(70 reference statements)

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“…Our finding supporting the association of CCL5 rs2107538 variant T, which may upregulate CCL5 expression ( 49 ), with protection against the development of CCC, led us to question the possible biological pathways for the induction of protection by CCL5 in Chagas heart disease. To shed light on this point, we analyzed the participation of CCL5 and its receptors CCR1 and CCR5 in CCC using an experimental model of C57BL/6 mice infected with the Colombian strain, which reproduces critical aspects of Chagas heart disease ( 28 , 37 , 40 , 41 ) and presents elevated levels of CCL5 in serum ( 55 ). Increased CCL5 levels were also detected in the cardiac tissue of chronically infected mice, corroborating the detection of enhanced CCL5 mRNA expression in this tissue ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

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

Batista

Alvarado-Arnez

Alves³

et al. 2018

Front. Immunol.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Batista

Alvarado-Arnez

Alves³

et al. 2018

Front. Immunol.

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“…Recently, Guedes-da-Silva et al ( 49 ) showed that antigens from the Y strain of T. cruzi are able to promote inflammatory neovascularization, probably induced by angiogenic mediators produced by macrophages ( 49 ). Furthermore, Shrestha et al ( 50 ) demonstrated that T. cruzi infection increases the inflammatory and angiogenic mediators in the heart of infected mice ( 50 ). Taking into account that the evolution of Chagas disease is linked to microvascular lesions, including obstruction due to thrombosis, perivascular inflammation, and lesions in the coronary arterioles ( 33 ), we believe that the increased neovascularization observed during T. cruzi infection may act as a delaying factor of the physiopathological mechanisms leading to the cardiac symptoms during the course of Chagas disease.…”

Section: Discussionmentioning

confidence: 99%

Treatment with a New Peroxisome Proliferator-Activated Receptor Gamma Agonist, Pyridinecarboxylic Acid Derivative, Increases Angiogenesis and Reduces Inflammatory Mediators in the Heart of Trypanosoma cruzi-Infected Mice

et al. 2017

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Trypanosoma cruzi infection induces an intense inflammatory response in diverse host tissues. The immune response and the microvascular abnormalities associated with infection are crucial aspects in the generation of heart damage in Chagas disease. Upon parasite uptake, macrophages, which are involved in the clearance of infection, increase inflammatory mediators, leading to parasite killing. The exacerbation of the inflammatory response may lead to tissue damage. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that exerts important anti-inflammatory effects and is involved in improving endothelial functions and proangiogenic capacities. In this study, we evaluated the intermolecular interaction between PPARγ and a new synthetic PPARγ ligand, HP24, using virtual docking. Also, we showed that early treatment with HP24, decreases the expression of NOS2, a pro-inflammatory mediator, and stimulates proangiogenic mediators (vascular endothelial growth factor A, CD31, and Arginase I) both in macrophages and in the heart of T. cruzi-infected mice. Moreover, HP24 reduces the inflammatory response, cardiac fibrosis and the levels of inflammatory cytokines (TNF-α, interleukin 6) released by macrophages of T. cruzi-infected mice. We consider that PPARγ agonists might be useful as coadjuvants of the antiparasitic treatment of Chagas disease, to delay, reverse, or preclude the onset of heart damage.

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“…In addition, the lard diet promoted a higher parasites load in both evaluated sites evaluated with the distinct pattern of CCL2 expression, after 48 h of the peak of parasitemia concerning Colombian strain of T. cruzi . At this representative moment of the experimental T. cruzi infection, no difference in inflammatory infiltration was detected through histological sections, but based on our previous experience, higher expression of CCL2 represents a higher release of this chemokine, an increasing of leukocyte recruitment, higher cardiac tissue damage and mortality in those infected animals ( 39 ).…”

Section: Discussionmentioning

confidence: 79%

Diet Rich in Lard Promotes a Metabolic Environment Favorable to Trypanosoma cruzi Growth

Souza

Silva

Farias

et al. 2021

Front. Cardiovasc. Med.

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Background:Trypanosoma cruzi is a protozoan parasite that causes Chagas disease and affects 6–7 million people mainly in Latin America and worldwide. Here, we investigated the effects of hyperlipidic diets, mainly composed of olive oil or lard on experimental T. cruzi infection. C57BL/6 mice were fed two different dietary types in which the main sources of fatty acids were either monounsaturated (olive oil diet) or saturated (lard diet).Methods: After 60 days on the diet, mice were infected with 50 trypomastigote forms of T. cruzi Colombian strain. We evaluated the systemic and tissue parasitism, tissue inflammation, and the redox status of mice after 30 days of infection.Results: Lipid levels in the liver of mice fed with the lard diet increased compared with that of the mice fed with olive oil or normolipidic diets. The lard diet group presented with an increased parasitic load in the heart and adipose tissues following infection as well as an increased expression of Tlr2 and Tlr9 in the heart. However, no changes were seen in the survival rates across the dietary groups. Infected mice receiving all diets presented comparable levels of recruited inflammatory cells at 30 days post-infection but, at this time, we observed lard diet inducing an overproduction of CCL2 in the cardiac tissue and its inhibition in the adipose tissue. T. cruzi infection altered liver antioxidant levels in mice, with the lard diet group demonstrating decreased catalase (CAT) activity compared with that of other dietary groups.Conclusions: Our data demonstrated that T. cruzi growth is more favorable on tissue of mice subjected to the lard diet. Our findings supported our hypothesis of a relationship between the source of dietary lipids and parasite-induced immunopathology.

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Expression and production of cardiac angiogenic mediators depend on the Trypanosoma cruzi-genetic population in experimental C57BL/6 mice infection

Cited by 11 publications

References 55 publications

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

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

Treatment with a New Peroxisome Proliferator-Activated Receptor Gamma Agonist, Pyridinecarboxylic Acid Derivative, Increases Angiogenesis and Reduces Inflammatory Mediators in the Heart of Trypanosoma cruzi-Infected Mice

Diet Rich in Lard Promotes a Metabolic Environment Favorable to Trypanosoma cruzi Growth

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