Chagasic cardiomyopathy (CCM), a major public health threat in Latin America and Mexico, is recognized as an emerging infectious disease in the U.S. Endomyocardial biopsies from patients in different clinical stages of the disease have suggested that myocardial inflammation and fibrosis play an important role in its pathogenesis. Because only a few, if any, parasites are detected during progressive CCM, other factors are believed involved in activation and/or sustaining the inflammatory response. These factors are, however, not known. We have shown in experimental models that infection by T. cruzi elicits mitochondrial dysfunction associated with oxidative modifications and altered activities of the respiratory chain complexes, generation of reactive oxygen species (ROS), and sustained oxidative damage in the myocardium. Our other studies show that antioxidant treatment is effective in limiting production of proinflammatory cytokines in cardiomyocytes, and recruitment of inflammatory cells in murine hearts infected by T. cruzi. In this project, we will determine 1) the pivotal role of mitochondrial ROS and respiratory chain deficiencies in eliciting the proinflammatory response in cardiomyocytes and subsequent recruitment of inflammatory cells in chagasic hearts, and 2) the biological significance of the mitochondrial redox-induced responses in cardiac dysfunction with progressive disease. Our central hypothesis is that T. cruzi-induced injuries of the mitochondrial membranes and respiratory complexes result in sustained ROS generation. These ROS are critical in sustaining oxidative stress and eliciting pro-inflammatory cytokines in cardiomyocytes, and thus provide stimuli for the consistent recruitment of inflammatory cells in chagasic hearts. Completion of the proposed project will provide a basic understanding of the role of mitochondrial ROS in initiating and/or sustaining pathological processes (inflammation, oxidative damage, fibrosis,) that contribute to cardiac dysfunction in CCM. Future molecular and mechanistic studies would determine whether therapies designed to manage the mitochondrial function or to enhance antioxidant defense capacity would effectively reduce severity of CCM.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wali, Tonu M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
Schools of Medicine
United States
Zip Code
Koo, Sue-Jie; Szczesny, Bartosz; Wan, Xianxiu et al. (2018) Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages. Front Immunol 9:202
Lopez, Marcos; Tanowitz, Herbert B; Garg, Nisha J (2018) Pathogenesis of Chronic Chagas Disease: Macrophages, Mitochondria, and Oxidative Stress. Curr Clin Microbiol Rep 5:45-54
Wen, Jake J; Garg, Nisha Jain (2018) Manganese superoxide dismutase deficiency exacerbates the mitochondrial ROS production and oxidative damage in Chagas disease. PLoS Negl Trop Dis 12:e0006687
Mesías, Andrea C; Sasoni, Natalia; Arias, Diego G et al. (2018) Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi. Free Radic Biol Med 130:23-34
Chowdhury, Imran H; Koo, Sue-Jie; Gupta, Shivali et al. (2017) Gene Expression Profiling and Functional Characterization of Macrophages in Response to Circulatory Microparticles Produced during Trypanosoma cruzi Infection and Chagas Disease. J Innate Immun 9:203-216
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
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
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
Gupta, Shivali; Garg, Nisha J (2015) A Two-Component DNA-Prime/Protein-Boost Vaccination Strategy for Eliciting Long-Term, Protective T Cell Immunity against Trypanosoma cruzi. PLoS Pathog 11:e1004828
Dey, Nilay; Sinha, Mala; Gupta, Shivali et al. (2014) Caspase-1/ASC inflammasome-mediated activation of IL-1?-ROS-NF-?B pathway for control of Trypanosoma cruzi replication and survival is dispensable in NLRP3-/- macrophages. PLoS One 9:e111539

Showing the most recent 10 out of 36 publications