Research Article: Immune Protection against Trypanosoma cruzi Induced by TcVac4 in a Canine Model

Date Published: April 8, 2015

Publisher: Public Library of Science

Author(s): José E. Aparicio-Burgos, José A. Zepeda-Escobar, Roberto Montes de Oca-Jimenez, José G. Estrada-Franco, Alberto Barbabosa-Pliego, Laucel Ochoa-García, Ricardo Alejandre-Aguilar, Nancy Rivas, Giovanna Peñuelas-Rivas, Margarita Val-Arreola, Shivali Gupta, Felix Salazar-García, Nisha J. Garg, Juan C. Vázquez-Chagoyán, Helton da Costa Santiago.

Abstract: Chagas disease, caused by Trypanosoma cruzi, is endemic in southern parts of the American continent. Herein, we have tested the protective efficacy of a DNA-prime/T. rangeli-boost (TcVac4) vaccine in a dog (Canis familiaris) model. Dogs were immunized with two-doses of DNA vaccine (pcDNA3.1 encoding TcG1, TcG2, and TcG4 antigens plus IL-12- and GM-CSF-encoding plasmids) followed by two doses of glutaraldehyde-inactivated T. rangeli epimastigotes (TrIE); and challenged with highly pathogenic T. cruzi (SylvioX10/4) isolate. Dogs given TrIE or empty pcDNA3.1 were used as controls. We monitored post-vaccination and post-challenge infection antibody response by an ELISA, parasitemia by blood analysis and xenodiagnosis, and heart function by electrocardiography. Post-mortem anatomic and pathologic evaluation of the heart was conducted. TcVac4 induced a strong IgG response (IgG2>IgG1) that was significantly expanded post-infection, and moved to a nearly balanced IgG2/IgG1 response in chronic phase. In comparison, dogs given TrIE or empty plasmid DNA only developed high IgG titers with IgG2 predominance in response to T. cruzi infection. Blood parasitemia, tissue parasite foci, parasite transmission to triatomines, electrocardiographic abnormalities were significantly lower in TcVac4-vaccinated dogs than was observed in dogs given TrIE or empty plasmid DNA only. Macroscopic and microscopic alterations, the hallmarks of chronic Chagas disease, were significantly decreased in the myocardium of TcVac4-vaccinated dogs. We conclude that TcVac4 induced immunity was beneficial in providing resistance to T. cruzi infection, evidenced by control of chronic pathology of the heart and preservation of cardiac function in dogs. Additionally, TcVac4 vaccination decreased the transmission of parasites from vaccinated/infected animals to triatomines.

Partial Text: Trypanosoma cruzi (T. cruzi) is a pathogenic protozoan that belongs to the Trypanosomatidae family. It is the etiologic agent of Chagas disease [1]. Approximately, 5% of the infected humans develop a lethal acute infection, and 30–40% progress to a chronic debilitating illness of the cardiac system, characterized by clinically irreversible and progressive myocardial hypertrophy and tissue destruction that eventually leads to heart failure [1]. It is an important health issue in most of the Latin American countries and due to human migration; it has become an important health issue in the United States and Europe [2]. Vector control programs have not been able to completely prevent parasite transmission [3]; the available anti-parasite drugs are not sufficiently safe or effective [4, 5]; and no vaccines are currently available.

In this study, we have tested the efficacy of a DNA-prime/TrIE-boost (TcVac4) vaccine in dogs. The candidate antigens TcG1, TcG2, and TcG4 used as DNA vaccine in the study are conserved in multiple, clinically-relevant isolates of T. cruzi, expressed in infective and intracellular stages of T. cruzi, recognized by antibody and T cell immunity in infected mice [8, 30], and recently shown to be serologically reactive in infected humans [31]. IL-12 and GM-CSF expression plasmids were used as adjuvants because these cytokines induce antigen presentation and B and T cell responses [32].



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