AUTHOR=Gupta Shivali , Salgado-Jiménez Berenice , Lokugamage Nandadeva , Vázquez-Chagoyán Juan Carlos , Garg Nisha Jain 

TITLE=TcG2/TcG4 DNA Vaccine Induces Th1 Immunity Against Acute Trypanosoma cruzi Infection: Adjuvant and Antigenic Effects of Heterologous T. rangeli Booster Immunization

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01456

DOI=10.3389/fimmu.2019.01456

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Chagas cardiomyopathy is caused by <italic>Trypanosoma cruzi</italic> (<italic>Tc</italic>). Two antigenic candidates, TcG2 and TcG4, are recognized by antibodies in naturally infected dogs and humans; and these vaccine candidates provided protection from <italic>Tc</italic> infection in mice and dogs. <italic>Trypanosoma rangeli</italic> (<italic>Tr</italic>) is non-pathogenic to mammals and shown to elicit cross-reactive anti-<italic>Tc</italic> antibodies. In this study, we investigated if fixed <italic>Tr</italic> (fTr) can further enhance the efficacy of the <italic>TcG2/TcG4</italic> DNA vaccine.</p><p><bold>Methods and Results:</bold> C57BL/6 mice were immunized with <italic>TcG2/TcG4</italic> DNA vaccine and fTr (delivered as an adjuvant or in prime-boost approach), and challenged with <italic>Tc</italic>. Serology studies showed that fTr (±quil-A) elicited <italic>Tc</italic>- and <italic>Tr-</italic>reactive IgGs that otherwise were not stimulated by <italic>TcG2/TcG4</italic> vaccine only, and quil-A had suppressive effects on fTr-induced IgGs. After challenge infection, <italic>TcG2/TcG4</italic>-vaccinated mice exhibited potent expansion of antigen- and <italic>Tc</italic>-specific IgGs that were not boosted by fTr±quil-A. Flow cytometry analysis showed that <italic>TcG2/TcG4</italic>-induced dendritic cells (DC) and macrophages (Mφ) responded to challenge infection by expression of markers of antigen uptake, processing, and presentation, and production of pro-inflammatory cytokines. <italic>TcG2/TcG4</italic>-induced CD4<sup>+</sup>T cells acquired Th1 phenotype and expressed markers that orchestrate adaptive immunity. A fraction of vaccine-induced CD4<sup>+</sup>T cells exhibited iTreg phenotype responsible for aversion of self-injurious immune responses. Further, <italic>TcG2/TcG4</italic>-vaccinated mice exhibited potent expansion of poly-functional CD8<sup>+</sup>T cells with TNF-α/IFN-γ production and cytolytic phenotype post-infection. Subsequently, tissue parasites and pathology were hardly detectable in <italic>TcG2/TcG4</italic>-vaccinated/infected mice. Inclusion of fTr±quil-A had no clear additive effects in improving the <italic>Tc</italic>-specific adaptive immunity and parasite control than was noted in mice vaccinated with <italic>TcG2/TcG4</italic> alone. Non-vaccinated mice lacked sufficient activation of Th1 CD4<sup>+</sup>/CD8<sup>+</sup>T cells, and exhibited &gt;10-fold higher levels of tissue parasite burden than was noted in vaccinated/infected mice.</p><p><bold>Conclusion:</bold><italic>TcG2/TcG4</italic> vaccine elicits highly effective immunity, and inclusion of fTr is not required to improve the efficacy of DNA vaccine against acute <italic>Tc</italic> infection in mice.</p>