Therapeutic Efficacy of a Subunit Vaccine in Controlling Chronic Trypanosoma cruzi Infection and Chagas Disease Is Enhanced by Glutathione Peroxidase Over-Expression.

Shivali Gupta,Nisha Jain Garg,Anahi De Jesus Delgadillo,Sarah Auclair,Charity Smith,Herbert B Tanowitz

doi:10.1371/journal.pone.0130562

Shivali Gupta, Nisha Jain Garg + Show 4 more

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https://doi.org/10.1371/journal.pone.0130562

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Journal: PloS one	Publication Date: Jun 15, 2015
Citations: 14	License type: CC BY 4.0

Affiliation: The University of Texas Medical Branch at Galveston

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.

Highlights

Chagas disease caused by Trypanosoma cruzi is endemic in Latin America and an emerging disease in the US and other developed countries
Mice immunized with the DNA-prime/protein-boost vaccine constituted of TcG1, TcG2 and TcG4 were capable of controlling challenge infection as evidenced by a 90–97% decline in acute parasitemia and tissue parasite burden; and, subsequently, inflammatory infiltrate and tissue fibrosis were absent in the heart and skeletal muscle of vaccinated mice [13]
We included GPx1tg mice in the study to determine if enhancing the cellular antioxidant status would alter the host’s resistance against chronic Chagas disease

Summary

Introduction

Chagas disease caused by Trypanosoma cruzi is endemic in Latin America and an emerging disease in the US and other developed countries. The current knowledge on protective immunity and vaccine development efforts against T. cruzi [5] and the pathologic role of oxidative stress in Chagas disease [4,6] have recently been reviewed. Several antigens, antigen-delivery vehicles, and adjuvants have been tested to elicit immune protection to T. cruzi in experimental animals (reviewed in [5,7,8,9]). Co-delivery of these antigens as a prophylactic vaccine elicited greater immunity and protection from T. cruzi infection than was noted with individual candidate antigens [11,12,13,14,15]. Mice immunized with the DNA-prime/protein-boost vaccine constituted of TcG1, TcG2 and TcG4 were capable of controlling challenge infection as evidenced by a 90–97% decline in acute parasitemia and tissue parasite burden; and, subsequently, inflammatory infiltrate and tissue fibrosis were absent in the heart and skeletal muscle of vaccinated mice [13]

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