EDECIO CUNHA NETO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/60 - Laboratório de Imunologia Clínica e Alergia, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/60 - Laboratório de Imunologia Clínica e Alergia, Hospital das Clínicas, Faculdade de Medicina - Líder
14 resultados
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- Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy(2018) CHEVILLARD, Christophe; NUNES, Joao Paulo Silva; FRADE, Amanda Farage; ALMEIDA, Rafael Ribeiro; PANDEY, Ramendra Pati; NASCIMENTO, Marilda Savoia; KALIL, Jorge; CUNHA-NETO, EdecioChagas disease is caused by infection with the protozoan Trypanosoma cruzi and affects over 8 million people worldwide. In spite of a powerful innate and adaptive immune response in acute infection, the parasite evades eradication, leading to a chronic persistent infection with low parasitism. Chronically infected subjects display differential patterns of disease progression. While 30% develop chronic Chagas disease cardiomyopathy (CCC)-a severe inflammatory dilated cardiomyopathy-decades after infection, 60% of the patients remain disease-free, in the asymptomatic/indeterminate (ASY) form, and 10% develop gastrointestinal disease. Infection of genetically deficient mice provided a map of genes relevant for resistance to T. cruzi infection, leading to the identification of multiple genes linked to survival to infection. These include pathogen resistance genes (PRG) needed for intracellular parasite destruction, and genes involved in disease tolerance (protection against tissue damage and acute phase death-DTG). All identified DTGs were found to directly or indirectly inhibit IFN-gamma production or Th1 differentiation. We hypothesize that the absolute need for DTG to control potentially lethal IFN-gamma PRG activity leads to T. cruzi persistence and establishment of chronic infection. IFN-gamma production is higher in CCC than ASY patients, and is the most highly expressed cytokine in CCC hearts. Key DTGs that downmodulate IFN-gamma, like IL-10, and Ebi3/IL27p28, are higher in ASY patients. Polymorphisms in PRG and DTG are associated with differential disease progression. We thus hypothesize that ASY patients are disease tolerant, while an imbalance of DTG and IFN-gamma PRG activity leads to the inflammatory heart damage of CCC.
- Mitochondria at the Crossroads of Immunity and Inflammatory Tissue Damage(2021) NUNES, Joao Paulo Silva; MORAES-VIEIRA, Pedro M.; CHEVILLARD, Christophe; CUNHA-NETO, Edecio
- SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease-2023(2023) MARIN-NETO, Jose Antonio; JR, Anis Rassi; OLIVEIRA, Glaucia Maria Moraes; CORREIA, Luis Claudio Lemos; RAMOS JUNIOR, Alberto Novaes; LUQUETTI, Alejandro Ostermayer; HASSLOCHER-MORENA, Alejandro Marcel; SOUSA, Andrea Silvestre de; PAOLA, Angelo Amato Vincenzo de; SOUSA, Antonio Carlos Sobral; RIBEIRO, Antonio Luiz Pinho; CORREIA FILHO, Dalmo; SOUZA, Dilma do Socorro Moraes de; CUNHA-NETO, Edecio; RAMIRES, Felix Jose Alvarez; BACAL, Fernando; NUNES, Maria do Carmo Pereira; MARTINELLI FILHO, Martino; SCANAVACCA, Maurici Ibrahim; SARAIVA, Roberto Magalhaes; OLIVEIRA JUNIOR, Wilson Alves de; LORGA-FILHO, Adalberto Menezes; GUIMARAES, Adriana de Jesus Benevides de Almeida; BRAGA, Adriana Lopes Latado; OLIVEIRA, Adriana Sarmento de; SARABANDA, Alvaro Valentim Lima; PINTO, Ana Yece das Neves; CARMO, Andre Assis Lopes do; SCHMIDT, Andre; COSTA, Andrea Rodrigues da; IANNI, Barbara Maria; MARKMAN FILHO, Brivaldo; ROCHITT, Carlos Eduardo; MACEDO, Carolina The; MADY, Charles; CHEVILLARD, Christophe; VIRGENS, Claudio Marcelo Bittencourt das; CASTRO, Cleudson Nery de; BRITTO, Constanca Felicia De Paoli de Carvalho; PISANI, Cristiano; RASSI, Daniel do Carmo; SOBRAL FILHO, Dario Celestino; ALMEIDA, Dirceu Rodrigues de; BOCCHI, Edimar Alcides; MESQUITA, Evandro Tinoco; MENDES, Fernanda de Souza Nogueira Sardinha; GONDIM, Francisca Tatiana Pereira; SILVA, Gilberto Marcelo Sperandio da; PEIXOTO, Giselle de Lima; LIMA, Gustavo Glotz de; VELOSO, Henrique Horta; MOREIRA, Henrique Turin; LOPES, Hugo Bellotti; PINTO, Ibraim Masciarelli Francisco; FERREIRA, Joao Marcos Bemfica Barbosa; NUNES, Joao Paulo Silva; BARRETO-FILHO, Jose Augusto Soares; SARAIVA, Jose Francisco Kerr; LANNES-VIEIRA, Joseli; OLIVEIRA, Joselina Luzia Menezes; ARMAGANIJAN, Luciana Vidal; MARTINS, Luiz Claudio; SANGENIS, Luiz Henrique Conde; BARBOSA, Marco Paulo Tomaz; ALMEIDA-SANTOS, Marcos Antonio; SIMOES, Marcos Vinicius; YASUDA, Maria Aparecida Shikanai; MOREIRA, Maria da Consolacao Vieira; HIGUCHI, Maria de Lourdes; MONTEIRO, Maria Rita de Cassia Costa; MEDIANO, Mauro Felippe Felix; LIMA, Mayara Maia; OLIVEIRA, Maykon Tavares de; ROMANO, Minna Moreira Dias; ARAUJO, Nadjar Nitz Silva Lociks de; MEDEIROS, Paulo de Tarso Jorge; ALVES, Renato Vieira; TEIXEIRA, Ricardo Alkmim; PEDROSA, Roberto Coury; ARAS JUNIOR, Roque; TORRES, Rosalia Morais; POVOA, Rui Manoel dos Santos; RASSI, Sergio Gabriel; ALVES, Silvia Marinho Martins; TAVARES, Suelene Brito do Nascimento; PALMEIRA, Swamy Lima; SILVA JUNIOR, Telemaco Luiz da; RODRIGUES, Thiago da Rocha; MADRINI JUNIOR, Vagner; BRANT, Veruska Maia da Costa; DUTRA, Walderez Ornelas; DIAS, Joao Carlos Pinto
- Recurrence of COVID-19 associated with reduced T-cell responses in a monozygotic twin pair(2022) V, Mateus de Castro; SANTOS, Keity S.; APOSTOLICO, Juliana S.; FERNANDES, Edgar R.; ALMEIDA, Rafael R.; LEVIN, Gabriel; MAGAWA, Jhosiene Y.; NUNES, Joao Paulo S.; BRUNI, Mirian; YAMAMOTO, Marcio M.; LIMA, Ariane C.; SILVA, Monize V. R.; MATOS, Larissa R. B.; CORIA, Vivian R.; CASTELLI, Erick C.; SCLIAR, Marilia O.; KURAMOTO, Andreia; BRUNO, Fernanda R.; JACINTHO, Lucas C.; NUNES, Kelly; WANG, Jaqueline Y. T.; COELHO, Veronica P.; NETO, Miguel Mitne; MACIEL, Rui M. B.; NASLAVSKY, Michel S.; PASSOS-BUENO, Maria Rita; BOSCARDIN, Silvia B.; ROSA, Daniela S.; KALIL, Jorge; ZATZ, Mayana; CUNHA-NETO, EdecioRecurrence of COVID-19 in recovered patients has been increasingly reported. However, the immune mechanisms behind the recurrence have not been thoroughly investigated. The presence of neutralizing antibodies (nAbs) in recurrence/reinfection cases suggests that other types of immune response are involved in protection against recurrence. Here, we investigated the innate type I/III interferon (IFN) response, binding and nAb assays and T-cell responses to severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) with IFN gamma (IFN gamma) enzyme-linked spot assay (ELISPOT) in three pairs of young adult monozygotic (MZ) twins with previous confirmed COVID-19, one of them presenting a severe recurrence four months after the initial infection. Twin studies have been of paramount importance to comprehend the immunogenetics of infectious diseases. Each MZ twin pair was previously exposed to SARS-CoV-2, as seen by clinical reports. The six individuals presented similar overall recovered immune responses except for the recurrence case, who presented a drastically reduced number of recognized SARS-CoV-2 T-cell epitopes on ELISPOT as compared to her twin sister and the other twin pairs. Our results suggest that the lack of a broad T-cell response to initial infection may have led to recurrence, emphasizing that an effective SARS-CoV-2-specific T-cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19.
- Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease(2021) OUARHACHE, Maryem; MARQUET, Sandrine; FRADE, Amanda Farage; FERREIRA, Ariela Mota; IANNI, Barbara; ALMEIDA, Rafael Ribeiro; NUNES, Joao Paulo Silva; FERREIRA, Ludmila Rodrigues Pinto; RIGAUD, Vagner Oliveira-Carvalho; CANDIDO, Darlan; MADY, Charles; ZANIRATTO, Ricardo Costa Fernandes; BUCK, Paula; TORRES, Magali; GALLARDO, Frederic; ANDRIEUX, Pauline; BYDLOWSKY, Sergio; LEVY, Debora; ABEL, Laurent; CARDOSO, Clareci Silva; SANTOS-JUNIOR, Omar Ribeiro; OLIVEIRA, Lea Campos; OLIVEIRA, Claudia Di Lorenzo; NUNES, Maria Do Carmo; COBAT, Aurelie; KALIL, Jorge; RIBEIRO, Antonio Luiz; SABINO, Ester Cerdeira; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheCardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-gamma and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. Methods We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. Results We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-gamma on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (Delta psi M), indicating mitochondrial dysfunction. Conclusion Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-gamma-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.
- miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy(2020) LAUGIER, Laurie; FERREIRA, Ludmila Rodrigues Pinto; FERREIRA, Frederico Moraes; CABANTOUS, Sandrine; FRADE, Amanda Farage; NUNES, Joao Paulo; RIBEIRO, Rafael Almeida; BROCHET, Pauline; TEIXEIRA, Priscila Camillo; SANTOS, Ronaldo Honorato Barros; BOCCHI, Edimar A.; BACAL, Fernando; CANDIDO, Darlan da Silva; MASO, Vanessa Escolano; NAKAYA, Helder I.; KALIL, Jorge; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheChronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFN gamma, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-gamma-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy. Author summary Chronic Chagas disease cardiomyopathy (CCC), an aggressive dilated cardiomyopathy caused by Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Little is known about the molecular mechanisms responsible for its severity. Authors study the possible role of microRNAs in the regulation of gene expression in relevant pathways and pathobiological processes. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) -small RNAs that can regulate gene expression-associated to severe cardiomyopathy development. The inflammatory mediator Interferon-gamma was the most likely inducer of gene expression in CCC, and most genes belonged to the immune response, fibrosis, hypertrophy and mitochondrial metabolism. A discrete number of differentially expressed mRNAs targeted a high number of differentially expressed mRNAs in multiple processes. Moreover, several pathways had multiple targets regulated by microRNAs, suggesting synergic effect. Results suggest that microRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue.
- Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients(2021) TEIXEIRA, Priscila Camillo; DUCRET, Axel; LANGEN, Hanno; NOGOCEKE, Everson; SANTOS, Ronaldo Honorato Barros; NUNES, Joao Paulo Silva; BENVENUTI, Luiz; LEVY, Debora; BYDLOWSKI, Sergio Paulo; BOCCHI, Edimar Alcides; TAKARA, Andreia Kuramoto; FIORELLI, Alfredo Inacio; STOLF, Noedir Antonio; POMERANZEFF, Pablo; CHEVILLARD, Christophe; KALIL, Jorge; CUNHA-NETO, EdecioChagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients' myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.
- 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, ChristopheChagas 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.
- Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy(2023) NUNES, Joao Paulo Silva; RODA, Vinicius Moraes de Paiva; ANDRIEUX, Pauline; KALIL, Jorge; CHEVILLARD, Christophe; CUNHA-NETO, EdecioChagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6 million people. About 30% of CD patients develop chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy that occurs decades after the initial infection, while most infected patients (60%) remain asymptomatic in the so-called indeterminate form (IF). Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are involved in the arrhythmia substrate and triggering events. Survival in CCC is worse than in other cardiomyopathies, which may be linked to a Th1-T cell rich myocarditis with abundant interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, selectively lower levels of mitochondrial energy metabolism enzymes in the heart, and reduced levels of high-energy phosphate, indicating poor adenosine triphosphate (ATP) production. IFN-gamma and TNF-alpha signaling, which are constitutively upregulated in CD patients, negatively affect mitochondrial function in cardiomyocytes, recapitulating findings in CCC heart tissue. Genetic studies such as whole-exome sequencing (WES) in nuclear families with multiple CCC/IF cases has disclosed rare heterozygous pathogenic variants in mitochondrial and inflammatory genes segregating in CCC cases. In this minireview, we summarized studies showing how IFN-gamma and TNF-alpha affect cell energy generation, mitochondrial health, and redox homeostasis in cardiomyocytes, in addition to human CD and mitochondria. We hypothesize that cytokine-induced mitochondrial dysfunction in genetically predisposed patients may be the underlying cause of CCC severity and we believe this mechanism may have a bearing on other inflammatory cardiomyopathies.
- Mitochondria as a Cellular Hub in Infection and Inflammation(2021) ANDRIEUX, Pauline; CHEVILLARD, Christophe; CUNHA-NETO, Edecio; NUNES, Joao Paulo SilvaMitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell's needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases.