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Projetos de Pesquisa
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LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina

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Agora exibindo 1 - 10 de 12
  • article 25 Citação(ões) na Scopus
    Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy
    (2013) FRADE, Amanda Farage; TEIXEIRA, Priscila Camilo; IANNI, Barbara Maria; PISSETTI, Cristina Wide; SABA, Bruno; WANG, Lin Hui Tzu; KURAMOTO, Andreia; NOGUEIRA, Luciana Gabriel; BUCK, Paula; DIAS, Fabricio; GINIAUX, Helene; LLORED, Agnes; ALVES, Sthefanny; SCHMIDT, Andre; DONADI, Eduardo; MARIN-NETO, Jose Antonio; HIRATA, Mario; SAMPAIO, Marcelo; FRAGATA, Abilio; BOCCHI, Edimar Alcides; STOLF, Antonio Noedir; FIORELLI, Alfredo Inacio; SANTOS, Ronaldo Honorato Barros; RODRIGUES, Virmondes; PEREIRA, Alexandre Costa; KALIL, Jorge; CUNHA-NETO, Edecio; CHEVILLARD, Christophe
    Aims: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while 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. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis. Methods and Results: We conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5' region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful. Conclusions: Genetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions.
  • article 42 Citação(ões) na Scopus
    TGFB1 and IL8 gene polymorphisms and susceptibility to visceral leishmaniasis
    (2011) FRADE, Amanda Farage; OLIVEIRA, Lea Campos de; COSTA, Dorcas Lamounier; COSTA, Carlos Henrique Nery; AQUINO, Dorlene; WEYENBERGH, Johan Van; BARRAL-NETTO, Manoel; BARRAL, Aldina; KALIL, Jorge; GOLDBERG, Anna Carla
    Visceral leishmaniasis (VL) or Kala-azar is a serious protozoan infectious disease caused by an obligate intracellular parasite. Cytokines have a major role in determining progression and severity of clinical manifestations in VL. We investigated polymorphisms in the TGFB1 and IL8 genes, which are cytokines known to have a role in onset and severity of the disease. Polymorphisms at TGFB1 -509 C/T and +869 T/C, and IL8 -251 A/T were analyzed by a PCR-RFLP technique, in 198 patients with VL, 98 individuals with asymptomatic infection positive for a delayed-type hypersensitivity test (DTH+) and in 101 individuals with no evidence of infection (DTH-). The presence of the T allele in position -509 of the TGFB1 gene conferred a two-fold risk to develop infection both when including those with clinical symptoms (DTH+ and VL, grouped) or when considering DTH+ only, respectively p = 0.007, OR = 1.9 [1.19-3.02] and p = 0.012, OR = 2.01 [1.17-3.79], when compared with DTH- individuals. In addition, occurrence of hemorrhage was associated with TGFB1 -509 T allele. We suggest that the -509 T allele of the TGFB1 gene, a cytokine with a biologically relevant role in the natural history of the disease, may contribute to overall susceptibility to infection by Leishmania and to severity of the clinical disease.
  • article 41 Citação(ões) na Scopus
    Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways
    (2013) FRADE, Amanda Farage; PISSETTI, Cristina Wide; IANNI, Barbara Maria; SABA, Bruno; LIN-WANG, Hui Tzu; NOGUEIRA, Luciana Gabriel; BORGES, Ariana de Melo; BUCK, Paula; DIAS, Fabricio; BARON, Monique; FERREIRA, Ludmila Rodrigues Pinto; SCHMIDT, Andre; MARIN-NETO, Jose Antonio; HIRATA, Mario; SAMPAIO, Marcelo; FRAGATA, Abilio; PEREIRA, Alexandre Costa; DONADI, Eduardo; KALIL, Jorge; RODRIGUES, Virmondes; CUNHA-NETO, Edecio; CHEVILLARD, Christophe
    Background: Chagas 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. Methods: Our 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. Results: The 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%. Conclusions: Our 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.
  • article 82 Citação(ões) na Scopus
    MicroRNAs miR-1, miR-133a, miR-133b, miR-208a and miR-208b are dysregulated in Chronic Chagas disease Cardiomyopathy
    (2014) FERREIRA, Ludmila Rodrigues Pinto; FRADE, Amanda Farage; SANTOS, Ronaldo Honorato Barros; TEIXEIRA, Priscila Camillo; BARON, Monique Andrade; NAVARRO, Isabela Cunha; BENVENUTI, Luiz Alberto; FIORELLI, Alfredo Inacio; BOCCHI, Edimar Alcides; STOLF, Noedir Antonio; CHEVILLARD, Christophe; KALIL, Jorge; CUNHA-NETO, Edecio
    Background/methods: Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi, and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs inmyocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified. Results: We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways. Conclusion: These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools.
  • article 22 Citação(ões) na Scopus
    Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease
    (2015) NOGUEIRA, Luciana Gabriel; FRADE, Amanda Farage; IANNI, Barbara Maria; LAUGIER, Laurie; PISSETTI, Cristina Wide; CABANTOUS, Sandrine; BARON, Monique; PEIXOTO, Gisele de Lima; BORGES, Ariana de Melo; DONADI, Eduardo; MARIN-NETO, Jose A.; SCHMIDT, Andre; DIAS, Fabricio; SABA, Bruno; WANG, Hui-Tzu Lin; FRAGATA, Abilio; SAMPAIO, Marcelo; HIRATA, Mario Hiroyuki; BUCK, Paula; MADY, Charles; MARTINELLI, Martino; LENSI, Mariana; SIQUEIRA, Sergio Freitas; PEREIRA, Alexandre Costa; RODRIGUES JR., Virmondes; KALIL, Jorge; CHEVILLARD, Christophe; CUNHA-NETO, Edecio
    Background: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the rest of the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described. IL-18 could potentially amplify the process by inducing increased expression of IFN-gamma which in turn can increase the production of IL-18, thereby creating a positive feedback mechanism. In order to assess the contribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the association between a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developing Chagas cardiomyopathy. Methods and results: We analyzed the rs2043055 marker in the 118 gene in a cohort of Chagas disease cardiomyopathy patients (n = 849) and asymptomatic subjects (n = 202). We found a significant difference in genotype frequencies among moderate and severe CCC patients with ventricular dysfunction. Conclusions: Our analysis suggests that the 118 rs2043055 polymorphism- or a SNP in tight linkage disequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome.
  • article 87 Citação(ões) na Scopus
    Myocardial Chemokine Expression and Intensity of Myocarditis in Chagas Cardiomyopathy Are Controlled by Polymorphisms in CXCL9 and CXCL10
    (2012) NOGUEIRA, Luciana Gabriel; SANTOS, Ronaldo Honorato Barros; IANNI, Barbara Maria; FIORELLI, Alfredo Inacio; MAIRENA, Eliane Conti; BENVENUTI, Luiz Alberto; FRADE, Amanda; DONADI, Eduardo; DIAS, Fabricio; SABA, Bruno; WANG, Hui-Tzu Lin; FRAGATA, Abilio; SAMPAIO, Marcelo; HIRATA, Mario Hiroyuki; BUCK, Paula; MADY, Charles; BOCCHI, Edimar Alcides; STOLF, Noedir Antonio; KALIL, Jorge; CUNHA-NETO, Edecio
    Background: Chronic 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 Results: Using 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.
  • article 3 Citação(ões) na Scopus
    Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy
    (2022) BROCHET, Pauline; IANNI, Barbara Maria; LAUGIER, Laurie; FRADE, Amanda Farage; NUNES, Joao Paulo Silva; TEIXEIRA, Priscila Camillo; MADY, Charles; FERREIRA, Ludmila Rodrigues Pinto; FERRE, Quentin; SANTOS, Ronaldo Honorato Barros; KURAMOTO, Andreia; CABANTOUS, Sandrine; STEFFEN, Samuel; STOLF, Antonio Noedir; POMERANTZEFF, Pablo; FIORELLI, Alfredo Inacio; BOCCHI, Edimar Alcides; PISSETTI, Cristina Wide; SABA, Bruno; CANDIDO, Darlan da Silva; DIAS, Fabricio C.; SAMPAIO, Marcelo Ferraz; GAIOTTO, Fabio Antonio; MARIN-NETO, Jose Antonio; FRAGATA, Abilio; ZANIRATTO, Ricardo Costa Fernandes; SIQUEIRA, Sergio; PEIXOTO, Giselle De Lima; RIGAUD, Vagner Oliveira-Carvalho; BACAL, Fernando; BUCK, Paula; ALMEIDA, Rafael Ribeiro; LIN-WANG, Hui Tzu; SCHMIDT, Andre; MARTINELLI, Martino; HIRATA, Mario Hiroyuki; DONADI, Eduardo Antonio; PEREIRA, Alexandre Costa; RODRIGUES JUNIOR, Virmondes; PUTHIER, Denis; KALIL, Jorge; SPINELLI, Lionel; CUNHA-NETO, Edecio; CHEVILLARD, Christophe
    Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.
  • article 7 Citação(ões) na Scopus
    Matrix Metalloproteinase 2 and 9 Enzymatic Activities are Selectively Increased in the Myocardium of Chronic Chagas Disease Cardiomyopathy Patients: Role of TIMPs
    (2022) BARON, Monique Andrade; FERREIRA, Ludmila Rodrigues Pinto; TEIXEIRA, Priscila Camillo; MORETTI, Ana Iochabel Soares; SANTOS, Ronaldo Honorato Barros; FRADE, Amanda Farage; KURAMOTO, Andreia; DEBBAS, Victor; BENVENUTI, Luiz Alberto; GAIOTTO, Fabio Antonio; BACAL, Fernando; POMERANTZEFF, Pablo; CHEVILLARD, Christophe; KALIL, Jorge; CUNHA-NETO, Edecio
    Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients.
  • article 39 Citação(ões) na Scopus
    Myocardial Infarction-Associated Transcript, a Long Noncoding RNA, Is Overexpressed During Dilated Cardiomyopathy Due to Chronic Chagas Disease
    (2016) FRADE, Amanda Farage; LAUGIER, Laurie; FERREIRA, Ludmila Rodrigues Pinto; BARON, Monique Andrade; BENVENUTI, Luiz Alberto; TEIXEIRA, Priscila Camillo; NAVARRO, Isabela Cunha; CABANTOUS, Sandrine; FERREIRA, Frederico Moraes; CANDIDO, Darlan da Silva; GAIOTTO, Fabio Antonio; BACAL, Fernando; POMERANTZEFF, Pablo; SANTOS, Ronaldo Honorato Barros; KALIL, Jorge; CUNHA-NETO, Edecio; CHEVILLARD, Christophe
    Long noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole-transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin-embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC.
  • article 7 Citação(ões) na Scopus
    Western blotting method (TESAcruzi) as a supplemental test for confirming the presence of anti-Trypanosoma cruzi antibodies in finger prick blood samples from children aged 0-5 years in Brazil
    (2011) FRADE, Amanda Farage; LUQUETTI, Alejandro O.; PRATA, Aluisio; FERREIRA, Antonio Walter
    Some Latin American countries have plans for total control and/or eradication of Chagas disease by the main vector (Triatoma infestans) and by blood transfusion. To achieve this, patients with Chagas disease must be identified. A Western blotting test, TESAcruzi, is described as a supplemental test for diagnosis of Chagas disease using samples collected from children <5 years living in different states of Brazil. Blood samples collected by finger prick on filter paper were sent to the test laboratory by a central laboratory to confirm results obtained previously. Ten percent of negative samples, all doubtful and all positive samples were received. Commercial reagents, IgG indirect immunofluorescence, enzyme immunoassay, and a recently introduced TESAcruzi test were used. From 8788 samples, 163 (1.85%) were reactive by IgG-ELISA and 312 (3.55%) by IgG IIF. From these, 77 (0.87%) were reactive in the TESAcruzi test. The results had high clinical value to identify those truly infected.