CVI Accepts, published online ahead of print on 18 March 2009

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Clin. Vaccine Immunol. doi:10.1128/CVI.00019-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

INCREASED MYELOPEROXIDASE ACTIVITY AND PROTEIN NITRATION ARE INDICATORS OF INFLAMMATION IN CHAGASIC PATIENTS

Monisha Dhiman, Jose Guillermo Estrada-Franco, Jasmine M Pando, Francisco J Ramirez-Aguilar, Heidi Spratt, Sara Vasquez-Corzo, Gladys Perez-Molina, Rosa Gallegos-Sandoval, Roberto Moreno, and Nisha Jain Garg^*

Departments of Microbiology and Immunology, Pathology, and Biochemistry and Molecular Biology University of Texas Medical Branch, Galveston TX 77555 USA; Laboratorio de Enfermedades Emergentes y Zoonóticas, Facultad de Ciencias Químicas-Campus IV, Universidad Autónoma de Chiapas, Tapachula, Chiapas, México; Chiapas State Health Services, and Instituto Mexicano del Seguro Social, Chiapas, Mexico; Member of The Institute for Human Infections and Immunity, The Center for Biodefense & Emerging Infectious Diseases, and The Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston TX 77555 USA

^* To whom correspondence should be addressed. Email: nigarg{at}utmb.edu.

In this study, we investigated whether inflammatory responses contribute to oxidative/nitrosative stress in chagasic patients. We used three tests (ELISA, immuno-flowcytometry, and STAT-PAK immuno-chromatography) to screen human sera samples (n = 1481) originating from Chiapas, Mexico for Trypanosoma cruzi-specific antibodies. We identified 121 subjects seropositive for T. cruzi-specific antibodies, a finding indicative of an 8.5% seroprevalence in the rural population from Chiapas. Seropositive and seronegative subjects were examined for plasma levels of biomarkers of inflammation, i.e., myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and xanthine oxidase (XOD); as well as for oxidative (advanced oxidation protein products, AOPPs) and nitrosative (3 nitrotyrosine, 3NT) biomarkers. The seropositive subjects exhibited a significant increase in MPO activity and protein level, the indicator of neutrophil activation. Subsequently, a corresponding increase in AOPP contents, formed by MPO-dependent hypochlorous acid and chloramine formation, was noted in seropositive subjects. The plasma level of 3NT was significantly increased in seropositive subjects, and yet we observed no change in XOD activity (O₂^•- source) and nitrate/nitrite contents (denotes iNOS activation and ^•NO production), which implied direct peroxynitrite formation does not contribute to increased nitrosative damage in chagasic subjects. Instead, a positive correlation between increased MPO activity and protein-3NT formation was observed, which suggested to us that MPO-dependent formation of nitrylchloridethat occurs in the presence of physiological ^•NO and O₂^•-concentrations, contributes to protein nitration. Overall, our data demonstrate that T. cruzi-induced neutrophil activation is pathologic, and contributes to MPO-mediated collateral protein oxidative and nitrosative damage in human chagasic patients. Therapies capable of suppressing MPO activity may be useful in controlling the inflammation and oxidative/nitrosative pathology in chagasic cardiomyopathy.