Our long term goal is to establish SaMi-Trop as a Center of Excellence for Neglected Infectious Disease Research in Brazil.
The Specific Aims of the current application are to begin that process by focusing on T. cruzi infection with the goal of finding an array of biomarkers that correlate with parasite persistence and Chagas cardiac disease that can be used to infer risk of disease progression and death as well used as surrogate markers of cure or efficacy of novel drugs. We will develop three interrelated studies: Project 1 will focus on applying gene expression tools to existing whole blood RNA samples from the NHLBI REDS-II cohort to discover and validate new biomarkers of active infection and disease progression, these will be combined with parasite specific (PCR load and antibody profiling and titers) and plasma proteomic biomarkers (chemokines, cytokines, and inflamatory, coagulation and cardiac parameters) that are being generated through already funded collaborations, to generate composite biomarker profiles and scores that coorelate with pre-defined disease stages. In Project 2 we plan to treat a subgroup of 100 T cruzi PCR-positive patients from the REDS-II cohort using standard treatment with benznidazole (BZN) and follow subjects for 2 years after treatment. We will use these samples to validate the utility of biomarkers and composite biomarker profiles found in project 1 for assessment of therapeutic responses including clearance or suppression of parasitemia or normalization of immune perturbations and markers of cardiac damage. In Project 3 we plan to take advantage of the Public Health System in the State of Minas by enrolling and collecting blood samples from 2000 Chagas disease patients. These patients will be followed for two years for the endpoints of death or admission to a hospital for cardiac disease. The main goal is to obtain a simple risk score based on biomarker levels and ECG fndings that could identify high risk patients in order to guide therapeutic approaches and serve as a foundation for future clinical trials. Two cores will be established: the Administrative Core and Database and Epidemiology Core that will support activities of the 3 projects, as well as create and sustain research training capacity for young Brazilian scientists.

Public Health Relevance

Chagas disease remains one of the most neglected diseases in the world, with 8-10 million infected people and only one marginally effective therapeutic. The lack of good biomarkers for active infection or clinical endpoints poses a problem for assessing the performance of new drugs or therapeutic interventions. This proposal will focus on the discovery and validation of Chagas biomarkers, as well as establish a center of excelence for Neglected Infectious Disease Research in Brazil.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center (P50)
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Special Emphasis Panel (ZAI1)
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Rao, Malla R
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Fundacao Faculdade de Medicina
Sao Paulo
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Zrein, Maan; Granjon, Elodie; Gueyffier, Lucie et al. (2018) A novel antibody surrogate biomarker to monitor parasite persistence in Trypanosoma cruzi-infected patients. PLoS Negl Trop Dis 12:e0006226
Ferreira, Ludmila Rodrigues Pinto; Ferreira, Frederico Moraes; Nakaya, Helder Imoto et al. (2017) Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction. J Infect Dis 215:387-395
Capuani, Ligia; Bierrenbach, Ana Luiza; Pereira Alencar, Airlane et al. (2017) Mortality among blood donors seropositive and seronegative for Chagas disease (1996-2000) in São Paulo, Brazil: A death certificate linkage study. PLoS Negl Trop Dis 11:e0005542
Ferreira, Ariela Mota; Sabino, Ester Cerdeira; de Oliveira, Lea Campos et al. (2016) Benznidazole Use among Patients with Chronic Chagas' Cardiomyopathy in an Endemic Region of Brazil. PLoS One 11:e0165950
Cardoso, Clareci Silva; Sabino, Ester Cerdeira; Oliveira, Claudia Di Lorenzo et al. (2016) Longitudinal study of patients with chronic Chagas cardiomyopathy in Brazil (SaMi-Trop project): a cohort profile. BMJ Open 6:e011181
Keating, S M; Deng, X; Fernandes, F et al. (2015) Inflammatory and cardiac biomarkers are differentially expressed in clinical stages of Chagas disease. Int J Cardiol 199:451-9
Tanowitz, Herbert B; Machado, Fabiana S; Spray, David C et al. (2015) Developments in the management of Chagas cardiomyopathy. Expert Rev Cardiovasc Ther 13:1393-409
Navarro, Isabela Cunha; Ferreira, Frederico Moraes; Nakaya, Helder I et al. (2015) MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes. PLoS Negl Trop Dis 9:e0003828
Carmo, Andre A L; Rocha, Manoel O C; Silva, Jose L P et al. (2015) Amiodarone and Trypanosoma cruzi parasitemia in patients with Chagas disease. Int J Cardiol 189:182-4
Capuani, Ligia; Bierrenbach, Ana Luiza; Abreu, Fatima et al. (2014) Accuracy of a probabilistic record-linkage methodology used to track blood donors in the Mortality Information System database. Cad Saude Publica 30:1623-32

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