MONIQUE ANDRADE BARON
Projetos de Pesquisa
Unidades Organizacionais
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina
5 resultados
Resultados de Busca
Agora exibindo 1 - 5 de 5
- 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.
- 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.
- 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.
- 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.
- 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.