MONIQUE ANDRADE BARON
Projetos de Pesquisa
Unidades Organizacionais
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina
9 resultados
Resultados de Busca
Agora exibindo 1 - 9 de 9
- The Combined Deficiency of Immunoproteasome Subunits Affects Both the Magnitude and Quality of Pathogen- and Genetic Vaccination-Induced CD8(+) T Cell Responses to the Human Protozoan Parasite Trypanosoma cruzi(2016) ERSCHING, Jonatan; VASCONCELOS, Jose R.; FERREIRA, Camila P.; CAETANO, Braulia C.; MACHADO, Alexandre V.; BRUNA-ROMERO, Oscar; BARON, Monique A.; FERREIRA, Ludmila R. P.; CUNHA-NETO, Edecio; ROCK, Kenneth L.; GAZZINELLI, Ricardo T.; RODRIGUES, Maurcio M.The beta 1i, beta 2i and beta 5i immunoproteasome subunits have an important role in defining the repertoire of MHC class I-restricted epitopes. However, the impact of combined deficiency of the three immunoproteasome subunits in the development of protective immunity to intracellular pathogens has not been investigated. Here, we demonstrate that immunoproteasomes play a key role in host resistance and genetic vaccination-induced protection against the human pathogen Trypanosoma cruzi (the causative agent of Chagas disease), immunity to which is dependent on CD8(+) T cells and IFN-gamma (the classical immunoproteasome inducer). We observed that infection with T. cruzi triggers the transcription of immunoproteasome genes, both in mice and humans. Importantly, genetically vaccinated or T. cruziinfected beta 1i, beta 2i and beta 5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8(+) effector T cells (CD8(+) CD44(high)CD62L(low)) specific for the previously characterized immunodominant (VNHRFTLV) H-2K(b)-restricted T. cruzi epitope. Not only the quantity, but also the quality of parasite-specific CD8(+) T cell responses was altered in TKO mice. Hence, the frequency of double-positive (IFN-gamma(+)/TNF+) or single-positive (IFN-gamma(+)) cells specific for the H-2K(b)-restricted immunodominant as well as subdominant T. cruzi epitopes were higher inWT mice, whereas TNF single-positive cells prevailed among CD8(+) T cells from TKO mice. Contrasting with their WT counterparts, TKO animals were also lethally susceptible to T. cruzi challenge, even after an otherwise protective vaccination with DNA and adenoviral vectors. We conclude that the immunoproteasome subunits are key determinants in host resistance to T. cruzi infection by influencing both the magnitude and quality of CD8(+) T cell responses.
- 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, ChristopheBackground: 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.
- 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, EdecioBackground/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.
- 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, EdecioBackground: 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.
- Induction of IL-12 Production in Human Peripheral Monocytes by Trypanosoma cruzi Is Mediated by Glycosylphosphatidylinositol-Anchored Mucin-Like Glycoproteins and Potentiated by IFN-gamma and CD40-CD40L Interactions(2014) ABEL, Lucia Cristina Jamli; FERREIRA, Ludmila Rodrigues Pinto; NAVARRO, Isabela Cunha; BARON, Monique Andrade; KALIL, Jorge; GAZZINELLI, Ricardo Tostes; RIZZO, Luiz Vicente; CUNHA-NETO, EdecioChagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-gamma secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products-like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)-are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-gamma primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-gamma. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins.
- MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes(2015) NAVARRO, Isabela Cunha; FERREIRA, Frederico Moraes; NAKAYA, Helder I.; BARON, Monique Andrade; VILAR-PEREIRA, Glaucia; PEREIRA, Isabela Resende; SILVA, Ana Maria Goncalves; REAL, Juliana Monte; BRITO, Thales De; CHEVILLARD, Christophe; LANNES-VIEIRA, Joseli; KALIL, Jorge; CUNHA-NETO, Edecio; FERREIRA, Ludmila Rodrigues PintoChagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.
- Ebi3 Prevents Trypanosoma cruzi-Induced Myocarditis by Dampening IFN-gamma-Driven Inflammation(2017) MEDINA, Tiago Silva; OLIVEIRA, Gabriela Goncalves; SILVA, Maria Claudia; DAVID, Bruna Araujo; SILVA, Grace Kelly; FONSECA, Denise Morais; SESTI-COSTA, Renata; FRADE, Amanda Farage; BARON, Monique Andrade; IANNI, Barbara; PEREIRA, Alexandre Costa; CHEVILLARD, Christophe; CUNHA-NETO, Edecio; MARIN-NETO, Jose Antonio; SILVA, Joao SantanaThe identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi-induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi. Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi-induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi-induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-gamma-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi-infected animals. Furthermore, in vivo IFN-gamma blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-gamma, the bona fide culprit of Chagas disease cardiomyopathy.
- 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, ChristopheLong 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.
- Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy(2017) LAUGIER, Laurie; FRADE, Amanda Farage; FERREIRA, Frederico Moraes; BARON, Monique Andrade; TEIXEIRA, Priscila Camillo; CABANTOUS, Sandrine; FERREIRA, Ludmila Rodrigues Pinto; LOUIS, Laurence; RIGAUD, Vagner Oliveira Carvalho; GAIOTTO, Fabio Antonio; BACAL, Fernando; POMERANTZEFF, Pablo; BOCCHI, Edimar; KALIL, Jorge; SANTOS, Ronaldo Honorato Barros; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheBackground. Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12 000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome. Methods. We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results. In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions. Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.