title: Therapeutic Efficacy of a Subunit Vaccine in Controlling Chronic Trypanosoma cruzi Infection and Chagas Disease Is Enhanced by Glutathione Peroxidase Over-Expression.
abstract: Trypanosoma cruzi-induced oxidative and inflammatory responses are implicated in chagasic cardiomyopathy. In this study, we examined the therapeutic utility of a subunit vaccine against T. cruzi and determined if glutathione peroxidase (GPx1, antioxidant) protects the heart from chagasic pathogenesis. C57BL/6 mice (wild-type (WT) and GPx1 transgenic (GPxtg) were infected with T. cruzi and at 45 days post-infection (dpi), immunized with TcG2/TcG4 vaccine delivered by a DNA-prime/Protein-boost (D/P) approach. The plasma and tissue-sections were analyzed on 150 dpi for parasite burden, inflammatory and oxidative stress markers, inflammatory infiltrate and fibrosis. WT mice infected with T. cruzi had significantly more blood and tissue parasite burden compared with infected/GPxtg mice (n = 5-8, p<0.01). Therapeutic vaccination provided >15-fold reduction in blood and tissue parasites in both WT and GPxtg mice. The increase in plasma levels of myeloperoxidase (MPO, 24.7%) and nitrite (iNOS activity, 45%) was associated with myocardial increase in oxidant levels (3-4-fold) and non-responsive antioxidant status in chagasic/WT mice; and these responses were not controlled after vaccination (n = 5-7). The GPxtg mice were better equipped than the WT mice in controlling T. cruzi-induced inflammatory and oxidative stress markers. Extensive myocardial and skeletal tissue inflammation noted in chagasic/WT mice, was significantly more compared with chagasic/GPxtg mice (n = 4-6, p<0.05). Vaccination was equally effective in reducing the chronic inflammatory infiltrate in the heart and skeletal tissue of infected WT and GPxtg mice (n = 6, p<0.05). Hypertrophy (increased BNP and ANP mRNA) and fibrosis (increased collagen) of the heart were extensively present in chronically-infected WT and GPxtg mice and notably decreased after therapeutic vaccination. We conclude the therapeutic delivery of D/P vaccine was effective in arresting the chronic parasite persistence and chagasic pathology; and GPx1 over-expression provided additive benefits in reducing the parasite burden, inflammatory/oxidative stress and cardiac remodeling in Chagas disease.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Shivali
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Charity
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Auclair
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Anahi De Jesus
authors.initials: Ade J
authors.lastname: Delgadillo
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America; Institute for Human Infections and Immunity and the Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Galveston, Texas, United States of America.
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002598:Chagas Cardiomyopathy / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D014355:Chagas Disease / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress / Q000276:immunology; D016052:Protozoan Vaccines / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D016052:Protozoan Vaccines; D017382:Reactive Oxygen Species; D022223:Vaccines, Subunit; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1