Genetic variants in the chemokines and chemokine receptors in Chagas disease

Flórez, Óscar; Martín, José Javier; González, Clara Isabel

doi:10.1016/j.humimm.2012.04.005

Cited by 34 publications

(60 citation statements)

References 46 publications

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“…The findings are in line with previous associations of chemokine or chemokine receptor polymorphisms in CCC (CCL2 [57], CCL5 [58], CCR5 [29], [58]. However, to our knowledge, is the first study to find gene polymorphisms associated to the transition to CCC with ventricular dysfunction, which is the most clinically relevant presentation of disease, the one associated with significant morbidity and mortality.…”

Section: Discussionsupporting

confidence: 91%

Myocardial Chemokine Expression and Intensity of Myocarditis in Chagas Cardiomyopathy Are Controlled by Polymorphisms in CXCL9 and CXCL10

et al. 2012

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BackgroundChronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium.Methods and ResultsUsing confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2–6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes.Conclusions Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC.

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Section: Discussionsupporting

confidence: 91%

Myocardial Chemokine Expression and Intensity of Myocarditis in Chagas Cardiomyopathy Are Controlled by Polymorphisms in CXCL9 and CXCL10

et al. 2012

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“…Although these SNPs were not studied before, is in line with the literature in studies performed in other Latin American countries with diverse ethnic compositions, where several SNPs were located in the 5′UTR of the CCR5 gene where they may influence binding of regulatory elements to gene expression control regions [22,47,48,61]. As suggested by Florez et al , these polymorphisms do not act independently [61]. Multiple polymorphic changes in the promoter may influence in a differential way the levels of CCR5 expression and the type of cell in which it is expressed.…”

Section: Resultssupporting

confidence: 69%

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

et al. 2013

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BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.MethodsOur genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.ResultsThe CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.ConclusionsOur data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.

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“…In humans, infection is characterized by 2 phases: an acute phase, which is generally asymptomatic, and a chronic phase, asymptomatic (indeterminate) or symptomatic T. cruzi genetic variability is increasingly recognized and this parasite has been genetically classified into six discrete typing units (DTUs) -TcI to TcVI (Zingales et al, 2009), -which have different geographic distributions and may be associated with geographically-restricted clinical profiles (Tibayrenc and Telleria, 2010). Several data indicate that human genetic determinants may impact the clinical outcome of Chagas disease (Florez et al, 2012;Vasconcelos et al, 2012). However, a role for genetic variability among the different parasite strains in the diverse clinical outcomes of Chagas disease cannot be excluded.…”

Section: Chagas Disease Is a Neglected Tropical Disease Caused By Thementioning

confidence: 99%

Trypanosoma cruzi strains cause different myocarditis patterns in infected mice

et al. 2014

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Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Acta Tropica 139 (2014) pancarditis with inflammatory infiltrates along the epicardium, whereas Sc43 caused inflammation preferentially in the auricles in association with intracellular parasite localization. We observed intramyocardic perivasculitis in mice infected with the VFRA and Y strains, but not with Sc43, during the acute phase, which suggests that endothelial cells may be involved in heart colonization by these more virulent strains. In in vitro infection assays, the Y strain had the highest parasite-cell ratio in epithelial, macrophage and endothelial cell lines, but Y and VFRA strains were higher than Sc43 in cardiomyocytes. Conclusions. This study supports parasite variability as a cause for the diverse cardiac outcomes observed in Chagas disease, and suggests that endothelial cells could be involved in heart infection during the acute phase.3

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Genetic variants in the chemokines and chemokine receptors in Chagas disease

Cited by 34 publications

References 46 publications

Myocardial Chemokine Expression and Intensity of Myocarditis in Chagas Cardiomyopathy Are Controlled by Polymorphisms in CXCL9 and CXCL10

Myocardial Chemokine Expression and Intensity of Myocarditis in Chagas Cardiomyopathy Are Controlled by Polymorphisms in CXCL9 and CXCL10

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

Trypanosoma cruzi strains cause different myocarditis patterns in infected mice

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