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
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conferenceObject Immune Responses Of CVID Patients To COVID-19 Vaccines(2023) MEDEIROS, Giuliana Xavier de; FERREIRA, Loisi de Carvalho Pereira; MAGAWA, Jhosiene Yukari; KURAMOTO, Andreia; SASAHARA, Greyce Luri; FERREIRA, Marcelo; BARROS, Myrthes Maragna Toledo; KALIL, Jorge; MARINHO, Ana Karolina Barreto Berselli; CUNHA-NETO, Edecio; SANTOS, Keity Souza; KOKRON, Cristina- 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.
- Myocardial gene and protein expression profiles after autoimmune injury in Chagas' disease cardiomyopathy(2011) CUNHA-NETO, Edecio; TEIXEIRA, Priscila C.; FONSECA, Simone G.; BILATE, Angelina M.; KALIL, JorgeOne third of the 16 million of individuals infected by the protozoan Trypanosoma cruzi in Latin America eventually develop chronic Chagas' disease cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy with shorter survival than non-inflammatory cardiomyopathies. The presence of a T cell-rich mononuclear inflammatory infiltrate and the relative scarcity of parasites in the heart suggested that chronic inflammation secondary to the autoimmune recognition of cardiac proteins could be a major pathogenetic mechanism. Sera from CCC patients crossreactively recognize cardiac myosin and T. cruzi protein B13. T cell clones elicited from peripheral blood with T. cruzi B13 protein or its peptides could crossreactively recognize epitopes from cardiac myosin heavy chain. Likewise, CD4+ T cell clones infiltrating CCC myocardium crossreactively recognize cardiac myosin and T. cruzi protein B13, and intralesional T cell lines produce the inflammatory cytokines IFN-gamma and TNF-alpha. Conversely, IFN-gamma-induced genes and chemokines were found to be upregulated in CCC heart samples, and IFN-gamma is able to induce cardiomyocyte expression of atrial natriuretic factor, a key member of the hypertrophy/heart failure signature. Proteomic analysis of CCC heart tissue showed reduced expression of the energy metabolism enzymes. It can be hypothesized that cytokine-induced modulation of cardiomyocyte gene/protein expression may be a novel disease mechanism in CCC, in addition to direct inflammatory damage.
conferenceObject Whole exome sequencing of Chagas disease cardiomyopathy families reveals accumulation of rare variants in mitochondrial and inflammation-associated genes(2019) CUNHA-NETO, E.; MARQUET, S.; FRADE, A. Farage; FERREIRA, A. Mota; OUARHACHE, M.; IANNI, B.; FERREIRA, L. Rodrigues Pinto; RIGAUD, V. Oliveira-Carvalho; ALMEIDA, R. Ribeiro; CANDIDO, D.; TORRES, M.; GALLARDO, F.; FERNANDES, R.; MADY, C.; BUCK, P.; CARDOSO, C.; SANTOS-JUNIOR, O. R.; OLIVEIRA, L. C.; OLIVEIRA, C. D. L.; NUNES, M. do Carmo; ABEL, L.; KALIL, J.; RIBEIRO, A. L. P.; SABINO, E. C.; CHEVILLARD, C.conferenceObject HIV CD4 Based Vaccine Increases CD8 T Cell Responses and Confers Protection Against Challenge with Recombinant Vaccinia Encoding HIV Gag-Pol Proteins(2013) RIBEIRO, S. P.; ROSA, D. S.; KALIL, J.; CUNHA-NETO, E.- 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.
conferenceObject Repurposed drugs acting on host mechanisms of T. cruzi invasion synergize with Benznidazole: New therapies for Chagas disease(2019) PANDEY, R. P.; NASCIMENTO, M. Savoia; BARRIOS, L.; GIBALDI, D.; LANNES-VIEIRA, J.; KALIL, J.; CUNHA-NETO, E.- Mitochondria at the Crossroads of Immunity and Inflammatory Tissue Damage(2021) NUNES, Joao Paulo Silva; MORAES-VIEIRA, Pedro M.; CHEVILLARD, Christophe; CUNHA-NETO, Edecio
- Myocardial Gene Expression of T-bet, GATA-3, Ror-gamma t, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed T(H)1-Type Response(2014) NOGUEIRA, Luciana Gabriel; SANTOS, Ronaldo Honorato Barros; FIORELLI, Alfredo Inacio; MAIRENA, Eliane Conti; BENVENUTI, Luiz Alberto; BOCCHI, Edimar Alcides; STOLF, Noedir Antonio; KALIL, Jorge; CUNHA-NETO, EdecioBackground. Chronic Chagas disease cardiomyopathy (CCC), a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (T(H)1/T(H)2/T(H)17/Treg) in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-gamma and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by T(H)2 cells (IL-4, IL-5, and IL-13) or associated with Treg (TGF-beta and IL-10) were not upregulated in CCC myocardium. Expression of T(H)1-related genes such as T-bet, IFN-gamma, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local T(H)1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3(+)CTLA4(+) Treg cell population, which is unable to completely curb IFN-gamma production in CCC myocardium, therefore fueling inflammation.
- CXCL9/Mig Mediates T cells Recruitment to Valvular Tissue Lesions of Chronic Rheumatic Heart Disease Patients(2013) FAE, Kellen C.; PALACIOS, Selma A.; NOGUEIRA, Luciana G.; OSHIRO, Sandra E.; DEMARCHI, Lea M. F.; BILATE, Angelina M. B.; POMERANTZEFF, Pablo M. A.; BRANDAO, Carlos; THOMAZ, Petronio G.; REIS, Maxwell dos; SAMPAIO, Roney; TANAKA, Ana C.; CUNHA-NETO, Edecio; KALIL, Jorge; GUILHERME, LuizaRheumatic fever (RF) is an autoimmune disease triggered by Streptococcus pyogenes infection frequently observed in infants from developing countries. Rheumatic heart disease (RHD), the major sequel of RF, leads to chronic inflammation of the myocardium and valvular tissue. T cells are the main population infiltrating cardiac lesions; however, the chemokines that orchestrate their recruitment are not clearly defined. Here, we investigated the expression of chemokines and chemokine receptors in cardiac tissue biopsies obtained from chronic RHD patients. Our results showed that CCL3/MIP1 alpha gene expression was upregulated in myocardium while CCL1/I-309 and CXCL9/Mig were highly expressed in valvular tissue. Auto-reactive T cells that infiltrate valvular lesions presented a memory phenotype (CD4(+)CD45RO(+)) and migrate mainly toward CXCL9/Mig gradient. Collectively, our results show that a diverse milieu of chemokines is expressed in myocardium and valvular tissue lesions and emphasize the role of CXCL9/Mig in mediating T cell recruitment to the site of inflammation in the heart.