Chagas disease is caused by the protozoan Trypanosoma cruzi, and represents the third greatest tropical disease burden globally. The total annual cost of Chagas disease management is estimated at >8 billion US dollars. The zoonotic presence of parasite and increased population mobility, transmission through blood transfusion, congenital infection and organ transplantation has, in recent years, increased the human cases of Chagas in the US. However, no vaccines or safe drugs are available for treatment of an estimated >300,000 patients in the US and >10 million patients in endemic countries. The studies in this project will identify therapeutic targets for the treatment of Chagasic cardiomyopathy. We pioneer the hypothesis that T. cruzi damages the heart tissue via three distinct mechanisms: (1) iCa+2 stress is caused by invading parasites, which results in alteration of mt membrane potential and initiates reactive oxygen species (ROS) release, (2) direct effects of parasite molecules promote survival of damaged host cells and cellular remodeling, and (3) persistence of inflammation-induced immunopathology, particularly due to reactive oxygen intermediates. These pathways converge, resulting in pathological hypertrophy leading to heart failure. The major preliminary observations that provide support to our hypothesis include (1) T. cruzi expression of antioxidants enhanced parasite virulence, (2) host sustains chronic oxidative/inflammatory stress that was contributory to impaired LV function during the progression of Chagas disease, and (3) ROS induced DNA oxidative adducts and poly(adenosine diphosphate ribose) polymerase 1 (PARP-1) activation signaled inflammatory cytokine response in infected cardiomyocytes. We will employ cutting-edge molecular, biochemical and immunological tools, established in the PI's laboratory, to achieve the following three aims - (1) Test the hypothesis that Tc-antioxidants prevent the normal homeostatic clearance of the damaged cells, and establish an environment conducive to fibrosis, (2) Test the hypothesis that PARP-1/PAR deregulates Nrf1/2 pathway and play a key role in chronic oxidative/inflammatory state of chagasic heart, and (3) Test the hypothesis that inhibition of PARP-1 will provide therapeutic benefits in preventing progression of chagasic cardiomyopathy. The innovation lies in the idea that the interaction of parasite (antioxidants) and host (PARP-1/Nrf1/2) molecules via abundant mitochondria in the cardiomyocytes is the key event resulting in chronic evolution of chagasic cardiomyopathy. These studies are significant and will demonstrate that therapeutic drugs against parasite (antioxidants) and host (PARP-1/PAR) factors will provide the most benefit in treatment of acute infection and preservation of heart function in chronically infected patients.

Public Health Relevance

This proposal will shed light on the cause and mechanisms of pathogenesis and cardiomyopathy outcome of infection by T. cruzi, and provide therapeutic targets to prevent the chronic inflammatory/oxidative pathology that is associated with morbidity and heart failure related deaths in endemic countries in Latin America and developed countries where migration of infected individuals has increased.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054578-09
Application #
8648965
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wali, Tonu M
Project Start
2003-04-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Wen, Jian-Jun; Wan, Xianxiu; Thacker, John et al. (2016) Chemotherapeutic efficacy of phosphodiesterase inhibitors in chagasic cardiomyopathy. JACC Basic Transl Sci 1:235-250
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Gupta, Shivali; Smith, Charity; Auclair, Sarah et al. (2015) Therapeutic Efficacy of a Subunit Vaccine in Controlling Chronic Trypanosoma cruzi Infection and Chagas Disease Is Enhanced by Glutathione Peroxidase Over-Expression. PLoS One 10:e0130562
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Wen, Jian-Jun; Nagajyothi, Fnu; Machado, Fabiana S et al. (2014) Markers of oxidative stress in adipose tissue during Trypanosoma cruzi infection. Parasitol Res 113:3159-65
Dey, Nilay; Sinha, Mala; Gupta, Shivali et al. (2014) Caspase-1/ASC inflammasome-mediated activation of IL-1β-ROS-NF-κB pathway for control of Trypanosoma cruzi replication and survival is dispensable in NLRP3-/- macrophages. PLoS One 9:e111539
Davies, Carolina; Dey, Nilay; Negrette, Olga Sanchez et al. (2014) Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with Benznidazole. PLoS Negl Trop Dis 8:e3231

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