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
106 resultados
Resultados de Busca
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- 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, ChristopheAims: 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.
- 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.
- 4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification(2023) KIYUNA, Ligia A.; CANDIDO, Darlan S.; BECHARA, Luiz R. G.; JESUS, Itamar C. G.; RAMALHO, Lisley S.; KRUM, Barbara; ALBUQUERQUE, Ruda P.; CAMPOS, Juliane C.; BOZI, Luiz H. M.; ZAMBELLI, Vanessa O.; ALVES, Ariane N.; CAMPOLO, Nicolas; MASTROGIOVANNI, Mauricio; BARTESAGHI, Silvina; LEYVA, Alejandro; DURAN, Rosario; RADI, Rafael; ARANTES, Guilherme M.; CUNHA-NETO, Edecio; MORI, Marcelo A.; CHEN, Che-Hong; YANG, Wenjin; MOCHLY-ROSEN, Daria; MACRAE, Ian J.; FERREIRA, Ludmila R. P.; FERREIRA, Julio C. B.Background and Aims Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure.Methods Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets.Results 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure.Conclusions 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure. Structured Graphical Abstract The vicious cycle of heart failure (HF). (i) Impaired aldehyde metabolism by aldehyde dehydrogenase 2 (ALDH2); (ii) accumulation of 4-hydroxynonenal (4-HNE), a reactive aldehyde by-product of mitochondrial dysfunction; (iii) direct 4-HNE inhibition of Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis; and (iv) overall impairment of miRNA biogenesis, which negatively impacts HF outcome. Blue and red arrows/inhibitors represent the vicious cycle of HF and the benefits of small molecule activators of ALDH2 in HF, respectively.
- Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial(2022) BAPTISTA, Marcella Vassao de Almeida; SILVA, Lais Teodoro da; SAMER, Sadia; OSHIRO, Telma Miyuki; SHYTAJ, Iart Luca; GIRON, Leila B.; PENA, Nathalia Mantovani; CRUZ, Nicolly; GOSUEN, Gisele Cristina; FERREIRA, Paulo Roberto Abrao; CUNHA-NETO, Edecio; GALINSKAS, Juliana; DIAS, Danilo; SUCUPIRA, Maria Cecilia Araripe; ALMEIDA-NETO, Cesar de; SALOMAO, Reinaldo; DUARTE, Alberto Jose da Silva; JANINI, Luis Mario; HUNTER, James R.; SAVARINO, Andrea; JULIANO, Maria Aparecida; DIAZ, Ricardo SobhieBackground: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-alpha and GM-CSF. After sequencing each patient's HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients' cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-gamma) production were measured in CD4(+) and CD8(+)T-cells. Results: The protocol of ex-vivo treatment with IFN-a and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4(+) and CD8(+)T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-gamma expression was significantly increased in CD4(+) T-cells. The number of candidates that increased in vitro the cytokine levels in CD4(+) and CD8(+)T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment.
- Mycobacterium tuberculosis epitope-specific interferon-gamma production in healthy Brazilians reactive and non-reactive to tuberculin skin test(2014) SILVA, Bosco Christiano Maciel da; GRASSI, Maria Fernanda Rios; COUTINHO, Raimundo; MASCARENHAS, Rita Elizabeth Moreira; OLAVARRIA, Viviana Nilla; COUTINHO-BORGO, Adriana; KALIL, Jorge; CUNHA-NETO, Edecio; FONSECA, Simone GoncalvesThe interferon (IFN)-gamma response to peptides can be a useful diagnostic marker of Mycobacterium tuberculosis (MTB) latent infection. We identified promiscuous and potentially protective CD4(+) T-cell epitopes from the most conserved regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2, phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm. Seven peptide sequences predicted to bind to multiple human leukocyte antigen (HLA)-DR molecules were synthesised and tested with IFN-gamma enzyme-linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from 16 Mantoux tuberculin skin test (TST)-positive and 16 TST-negative healthy donors. Eighty-eight percent of TST-positive donors responded to at least one of the peptides, compared to 25% of TST-negative donors. Each individual peptide induced IFN-gamma production by PBMCs from at least 31% of the TST-positive donors. The magnitude of the response against all peptides was 182 +/- 230 x 10(6) IFN-gamma spot forming cells (SFC) among TST-positive donors and 36 +/- 62 x 10(6) SFC among TST-negative donors (p = 0.007). The response to GroEL2 (463-477) was only observed in the TST-positive group. This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort of individuals with latent tuberculosis (TB) to evaluate its potential to diagnose latent TB and it may be included in ELISPOT-based IFN-gamma assays to identify individuals with this condition.
- CD4+T cells from HIV-1-infected patients recognize wild-type and mutant human immunodeficiency virus-1 protease epitopes(2011) MULLER, N. G.; ALENCAR, R.; JAMAL, L.; HAMMER, J.; SIDNEY, J.; SETTE, A.; BRINDEIRO, R. M.; KALIL, J.; CUNHA-NETO, E.; MORAES, S. L.P>Human immunodeficiency virus (HIV)-1 protease is a known target of CD8+ T cell responses, but it is the only HIV-1 protein in which no fully characterized HIV-1 protease CD4 epitopes have been identified to date. We investigated the recognition of HIV-1 protease by CD4+ T cells from 75 HIV-1-infected, protease inhibitor (PI)-treated patients, using the 5,6-carboxyfluorescein diacetate succinimidyl ester-based proliferation assay. In order to identify putative promiscuous CD4+ T cell epitopes, we used the TEPITOPE algorithm to scan the sequence of the HXB2 HIV-1 protease. Protease regions 4-23, 45-64 and 73-95 were identified; 32 sequence variants of the mentioned regions, encoding frequent PI-induced mutations and polymorphisms, were also tested. On average, each peptide bound to five of 15 tested common human leucocyte antigen D-related (HLA-DR) molecules. More than 80% of the patients displayed CD4+ as well as CD8+ T cell recognition of at least one of the protease peptides. All 35 peptides were recognized. The response was not associated with particular HLA-DR or -DQ alleles. Our results thus indicate that protease is a frequent target of CD4+ along with CD8+ proliferative T cell responses by the majority of HIV-1-infected patients under PI therapy. The frequent finding of matching CD4+ and CD8+ T cell responses to the same peptides may indicate that CD4+ T cells provide cognate T cell help for the maintenance of long-living protease-specific functional CD8+ T cells.
- Polymorphism in the catalytic subunit of the PI3K gamma gene is associated with Trypanosoma cruzi-induced chronic chagasic cardiomyopathy(2021) SILVA, Maria Claudia; MEDINA, Tiago da Silva; FUZO, Carlos Alessandro; DIAS, Fabricio Cesar; FREITAS-CASTRO, Felipe; FUKUTANI, Kiyoshi Ferreira; DONADI, Eduardo Antonio; CUNHA-NETO, Edecio; CUNHA, Thiago Mattar; SILVA, Joao SantanaChagas disease is caused by the protozoan parasite Trypanosoma cruzi. During the chronic phase of disease, while most infected people do not present symptoms, characterizing the asymptomatic form, some patients develop the cardiac form or chronic chagasic cardiomyopathy, which is considered the most severe manifestation of this disease. Considering that the activation of the PI3K gamma signaling pathway is essential for an efficient immune response against T. cruzi infection, we evaluated the PIK3CG C > T (rs1129293) polymorphism in exon 3 of this gene, which encodes the catalytic subunit of PI3K gamma. The PIK3CG CT and TT genotypes were found to be associated with an increased risk of developing the cardiac form of the disease rather than the asymptomatic or digestive forms. In conclusion, the presence of the T allele at single or double doses may differentiate the cardiac from other clinical manifestations of Chagas disease. This finding should help in further studies to evaluate the mechanisms underlying the differential association of PIK3CG in Chagas disease.
- The CD8(+) Memory Stem T Cell (T-SCM) Subset Is Associated with Improved Prognosis in Chronic HIV-1 Infection(2014) RIBEIRO, Susan P.; MILUSH, Jeffrey M.; CUNHA-NETO, Edecio; KALLAS, Esper G.; KALIL, Jorge; SOMSOUK, Ma; HUNT, Peter W.; DEEKS, Steven G.; NIXON, Douglas F.; SENGUPTA, DeviMemory stem T cells (T-SCM) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4(+) T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the T-SCM compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8(+) T-SCM was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4(+) T-SCM cells among all of the infected groups. The frequency of CD4(+) T-SCM predicted higher CD8(+) T-SCM frequencies, consistent with a role for the CD4(+) subset in helping to maintain CD8(+) memory T cells. In addition, T-SCM appeared to be progenitors for effector T cells (TEM), as these two compartments were inversely correlated. Increased frequencies of CD8(+) T-SCM predicted lower viral loads, higher CD4(+) counts, and less CD8(+) T cell activation. Finally, we found that T-SCM express the mucosal homing integrin alpha(4)beta(7) and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4(+) T-SCM was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4(+) T cell depletion. IMPORTANCE HIV-1 infection leads to profound impairment of the immune system. T-SCM constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8(+) T-SCM compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8(+) T-SCM and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8(+) T-SCM population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of T-SCM.
- Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells(2018) CAIRES JR., Luiz Carlos de; GOULART, Ernesto; MELO, UiraSouto; ARAUJO, Bruno Silva Henrique; ALVIZI, Lucas; SCHANOSKI, Alessandra Soares; OLIVEIRA, Danyllo Felipe de; KOBAYASHI, Gerson Shigeru; GRIESI-OLIVEIRA, Karina; MUSSO, Camila Manso; AMARAL, MuriloSena; DASILVA, Lucas Ferreira; ASTRAY, Renato Mancini; SUAREZ-PATINO, Sandra Fernanda; VENTINI, Daniella Cristina; SILVA, Sergio Gomes da; YAMAMOTO, Guilherme Lopes; EZQUINA, Suzana; NASLAVSKY, Michel Satya; SILVA, Kayque Telles Alves; WEINMANN, Karina; LINDEN, Vanessa Van der; LINDEN, Helio Van der; OLIVEIRA, Joao Mendes Ricardo de; ARRAIS, Nivia Rodrigues Maria; MELO, Adriana; FIGUEIREDO, Thalita; SANTOS, Silvana; MEIRA, Joanna Castro Goes; PASSOS, Saulo Duarte; ALMEIDA, Roque Pacheco de; BISPO, Ana JovinaBarreto; CAVALHEIRO, EsperAbrao; KALIL, Jorge; CUNHA-NETO, Edecio; NAKAYA, Helder; SANTOS, Robert Andreata; FERREIRA, Luis Carlos de Souza; VERJOVSKI-ALMEIDA, Sergio; HO, Paulo Lee; PASSOS-BUENO, Maria Rita; ZATZ, MayanaCongenital Zika syndrome (CZS) causes early brain development impairment by affecting neural progenitor cells (NPCs). Here, we analyze NPCs from three pairs of dizygotic twins discordant for CZS. We compare by RNA-Seq the NPCs derived from CZS-affected and CZS-unaffected twins. Prior to Zika virus (ZIKV) infection the NPCs from CZS babies show a significantly different gene expression signature of mTOR and Wnt pathway regulators, key to a neurodevelopmental program. Following ZIKV in vitro infection, cells from affected individuals have significantly higher ZIKV replication and reduced cell growth. Whole-exome analysis in 18 affected CZS babies as compared to 5 unaffected twins and 609 controls excludes a monogenic model to explain resistance or increased susceptibility to CZS development. Overall, our results indicate that CZS is not a stochastic event and depends on NPC intrinsic susceptibility, possibly related to oligogenic and/or epigenetic mechanisms.
- Changes in Neuropsychological Tests and Brain Metabolism After Bariatric Surgery(2014) MARQUES, Emerson Leonildo; HALPERN, Alfredo; MANCINI, Marcio Correa; MELO, Maria Edna de; HORIE, Ndia Celeste; BUCHPIGUEL, Carlos Alberto; COUTINHO, Artur Martins Novaes; ONO, Carla Rachel; PRANDO, Silvana; SANTO, Marco Aurelio; CUNHA-NETO, Edecio; FUENTES, Daniel; CERCATO, CintiaContext: The mechanisms by which obesity alters the cerebral function and the effect of weight loss on the brain have not been completely clarified. Objective: The objective of the study was to assess the effect of bariatric surgery on the cognitive function and cerebral metabolism. Design: Seventeen obese women were studied prior to and 24 weeks after bariatric surgery using neuropsychological tests and positron emission tomography. Setting: The study was conducted in a reference center for the treatment of obesity of a Brazilian public university. Participants: Thirty-three women paired by age and level of education made up two groups: 17 severely obese patients and 16 lean patients. They did not have diabetes mellitus or a family history of dementia. Main Outcome Measures: Comparison of performance in neuropsychological tests and cerebral metabolism of the obese women before and after bariatric surgery was measured. The results found at the two moments were compared with those of the women of normal weight. Results: Women with a mean age of 40.5 years and mean body mass index of 50.1 kg/m(2) when compared with women with mean body mass index of 22.3 kg/m(2) showed increased cerebral metabolism, especially in the posterior cingulate gyrus (P <.004). No difference was found between the groups for the neuropsychological tests. After 24 weeks the cerebral metabolism of the obese women was lower, similar to the lean women, and there was an improvement of executive function, accompanying changes of metabolic and inflammatory parameters. Conclusions: Obese women may have increased cerebral metabolism when compared with women of normal weight, and this appears to reverse after weight loss induced by bariatric surgery, accompanied by improved executive function.