Identification of predictive / prognostic genetic signature in Chagas cardiomyopathy: a systems biology approach

• Grant number: 13/50302-3
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2013
• End date: December 31, 2017
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Agreement: ANR - Blanc
• Principal Investigator: Edecio Cunha Neto
• Grantee: Edecio Cunha Neto
• Principal researcher abroad: Christophe Chevillard
• Institution abroad: Aix-Marseille Université (AMU), France
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Chagas disease, caused by Trypanosoma cruzi, affects 15 million people; from these, 30% develop myocarditis and Chronic Chagas disease cardiomyopathy (CCC) while most patients remain asymptomatic (ASY). Familial aggregation of CCC cases and the association of single nucleotide polymorphisms (SNP) with CCC suggests a genetic component to disease susceptibility. The outcome of Chagas disease is ultimately defined in the patients' hearts, a consequence of inflammation and myocardial response. We hypothesize that expression of many pathogenetically relevant genes/ proteins in the myocardium of CCC patients is controlled by genetic polymorphisms, and that a genetic signature based on such polymorphic genes can have a prognostic value. In Aim 1, we will use a systems biology approach to identify genes/proteins differentially expressed in CCC myocardium, using proteomic and transcriptomic analysis. In aim 2, we will identify genetic variants associated to disease. A case-control study will use large main and replication cohorts (CCC cases and ASY controls). Common Tag single SNP from genes identified in Aim 1 will be genotyped and analyzed. Exome sequencing will be used in multicase nuclear families, to identify rare variants shared only by CCC cases. Functional analyses on SNPs will be performed. Combinations of multiple SNPs may have a prognostic value at the individual patient levei, allowing close follow-up. Moreover, this study will provide significant information on pathogenesis and disease progression. (AU)

Scientific publications

(15)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CUNHA-NETO, EDECIO; ROSA, DANIELA S.; HARRIS, PAUL E.; OLSON, TIM; MORROW, ALEX; CIOTLOS, SERBAN; HERST, CHARLES V.; RUBSAMEN, REID MARTIN. An Approach for a Synthetic CTL Vaccine Design against Zika Flavivrus Using Class I and Class II Epitopes Identified by Computer Modeling. FRONTIERS IN IMMUNOLOGY, v. 8, JUN 9 2017. (13/50302-3)

OUARHACHE, MARYEM; MARQUET, SANDRINE; FRADE, AMANDA FARAGE; FERREIRA, ARIELA MOTA; IANNI, BARBARA; ALMEIDA, RAFAEL RIBEIRO; SILVA NUNES, JOAO PAULO; PINTO FERREIRA, LUDMILA RODRIGUES; RIGAUD, VAGNER OLIVEIRA-CARVALHO; CANDIDO, DARLAN; et al. Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease. JOURNAL OF CLINICAL IMMUNOLOGY, v. 41, n. 5, p. 1048-1063, JUL 2021. (14/50890-5, 13/50302-3)

NUNES, JOAO PAULO SILVA; MORAES-VIEIRA, PEDRO M.; CHEVILLARD, CHRISTOPHE; CUNHA-NETO, EDECIO. Mitochondria at the Crossroads of Immunity and Inflammatory Tissue Damage. FRONTIERS IN IMMUNOLOGY, v. 12, p. 3-pg., 2021-11-30. (14/50890-5, 15/15626-8, 13/50302-3, 19/25973-8, 19/19435-3)

BROCHET, PAULINE; IANNI, BARBARA; NUNES, JOAO P. S.; FRADE, AMANDA F.; TEIXEIRA, PRISCILA C.; MADY, CHARLES; FERREIRA, LUDMILA R. P.; KURAMOTO, ANDREIA; PISSETTI, CRISTINA W.; SABA, BRUNO; et al. Blood DNA methylation marks discriminate Chagas cardiomyopathy disease clinical forms. FRONTIERS IN IMMUNOLOGY, v. 13, p. 6-pg., 2022-09-29. (14/50890-5, 13/50302-3)

NAVARRO, ISABELA CUNHA; FERREIRA, FREDERICO MORAES; NAKAYA, HELDER I.; BARON, MONIQUE ANDRADE; VILAR-PEREIRA, GLAUCIA; PEREIRA, ISABELA RESENDE; GONCALVES SILVA, ANA MARIA; REAL, JULIANA MONTE; DE BRITO, THALES; CHEVILLARD, CHRISTOPHE; et al. MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes. PLoS Neglected Tropical Diseases, v. 9, n. 6, JUN 2015. (13/50302-3, 12/08107-6)

PINTO FERREIRA, LUDMILA RODRIGUES; FRADE, AMANDA FARAGE; BARROS SANTOS, RONALDO HONORATO; TEIXEIRA, PRISCILA CAMILLO; BARON, MONIQUE ANDRADE; NAVARRO, ISABELA CUNHA; BENVENUTI, LUIZ ALBERTO; FIORELLI, ALFREDO INACIO; BOCCHI, EDIMAR ALCIDES; STOLF, NOEDIR ANTONIO; et al. MicroRNAs miR-1, miR-133a, miR-133b, miR-208a and miR-208b are dysregulated in Chronic Chagas disease Cardiomyopathy. INTERNATIONAL JOURNAL OF CARDIOLOGY, v. 175, n. 3, p. 409-417, AUG 20 2014. (08/57881-0, 13/50302-3, 12/08107-6)

LAUGIER, LAURIE; FRADE, AMANDA FARAGE; FERREIRA, FREDERICO MORAES; BARON, MONIQUE ANDRADE; TEIXEIRA, PRISCILA CAMILLO; CABANTOUS, SANDRINE; PINTO FERREIRA, LUDMILA RODRIGUES; LOUIS, LAURENCE; CARVALHO RIGAUD, VAGNER OLIVEIRA; GAIOTTO, FABIO ANTONIO; et al. Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy. Clinical Infectious Diseases, v. 65, n. 7, p. 1103-1111, OCT 1 2017. (13/50302-3)

BROCHET, PAULINE; IANNI, BARBARA MARIA; LAUGIER, LAURIE; FRADE, AMANDA FARAGE; SILVA NUNES, JOAO PAULO; TEIXEIRA, PRISCILA CAMILLO; MADY, CHARLES; FERREIRA, LUDMILA RODRIGUES PINTO; FERRE, QUENTIN; SANTOS, RONALDO HONORATO BARROS; et al. Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy. FRONTIERS IN IMMUNOLOGY, v. 13, p. 16-pg., 2022-08-22. (14/50890-5, 13/50302-3)

CHEVILLARD, CHRISTOPHE; NUNES, JOAO PAULO SILVA; FRADE, AMANDA FARAGE; ALMEIDA, RAFAEL RIBEIRO; PANDEY, RAMENDRA PATI; NASCIMENTO, MARILDA SAVOIA; KALIL, JORGE; CUNHA-NETO, EDECIO. Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy. FRONTIERS IN IMMUNOLOGY, v. 9, DEC 3 2018. (16/15209-0, 13/50302-3, 14/50890-5)

RIBEIRO, SUSAN PEREIRA; DE MOURA MATTARAIA, VANIA GOMES; ALMEIDA, RAFAEL RIBEIRO; GHIURO VALENTINE, ELIZABETH JULIANA; SALES, NATIELY SILVA; FERREIRA, LUIS CARLOS S.; SA-ROCHA, LUIZ CARLOS; JACINTHO, LUCAS CAUE; SANTANA, VINICIUS CANATO; SIDNEY, JOHN; et al. promiscuous T cell epitope-based HIV vaccine providing redundant population coverage of the HLA class II elicits broad, polyfunctional T cell responses in nonhuman primate. Vaccine, v. 40, n. 2, p. 239-246, JAN 21 2022. (14/50890-5, 13/50302-3)

PINTO FERREIRA, LUDMILA RODRIGUES; CORREIA, CRISTIANO JESUS; ZANONI, FERNANDO LUIZ; CARVALHO-SILVA, ANA CAROLINA; ZANIRATTO, RICARDO; CANDIDO, DARLAN DA SILVA; ALMEIDA, RAFAEL RIBEIRO; BREITHAUPT-FALOPPA, ANA CRISTINA; CUNHA-NETO, EDECIO; MOREIRA, LUIZ FELIPE P.. ardiac MicroRNA Expression Profile After Experimental Brain Death Is Associated With Myocardial Dysfunction and Can Be Modulated by Hypertonic Salin. TRANSPLANTATION, v. 106, n. 2, p. 289-298, FEB 2022. (13/50302-3, 12/19841-2, 14/50890-5)

PINTO FERREIRA, LUDMILA RODRIGUES; FERREIRA, FREDERICO MORAES; LAUGIER, LAURIE; CABANTOUS, SANDRINE; NAVARRO, ISABELA CUNHA; CANDIDO, DARLAN DA SILVA; RIGAUD, VAGNER CARVALHO; REAL, JULIANA MONTE; PEREIRA, GLAUCIA VILAR; PEREIRA, ISABELA RESENDE; et al. Integration of miRNA and gene expression profiles suggest a role for miRNAs in the pathobiological processes of acute Trypanosoma cruzi infection. SCIENTIFIC REPORTS, v. 7, DEC 21 2017. (13/50302-3)

PINTO FERREIRA, LUDMILA RODRIGUES; FERREIRA, FREDERICO MORAES; NAKAYA, HELDER IMOTO; DENG, XUTAO; CNDIDO, DARLAN DA SILVA; DE OLIVEIRA, LEA CAMPOS; BILLAUD, JEAN-NOEL; LANTERI, MARION C.; RIGAUD, VAGNER OLIVEIRA-CARVALHO; SEIELSTAD, MARK; et al. Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction. Journal of Infectious Diseases, v. 215, n. 3, p. 387-395, FEB 1 2017. (13/50302-3)

ANDRIEUX, PAULINE; CHEVILLARD, CHRISTOPHE; CUNHA-NETO, EDECIO; NUNES, JOAO PAULO SILVA. Mitochondria as a Cellular Hub in Infection and Inflammation. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 21, NOV 2021. (14/50890-5, 13/50302-3)

NUNES, JOAO PAULO SILVA; ANDRIEUX, PAULINE; BROCHET, PAULINE; ALMEIDA, RAFAEL RIBEIRO; KITANO, EDUARDO; HONDA, ANDRE KENJI; IWAI, LEO KEI; ANDRADE-SILVA, DEBORA; GOUDENEGE, DAVID; ALCANTARA SILVA, KARLA DEYSIREE; et al. Co-Exposure of Cardiomyocytes to IFN-gamma and TNF-alpha Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy. FRONTIERS IN IMMUNOLOGY, v. 12, NOV 11 2021. (14/50890-5, 13/50302-3)