Trypanosoma cruzi 80 kDa prolyl oligopeptidase (Tc80) as a novel immunogen for Chagas disease vaccine

Abstract

BackgroundChagas disease, also known as American Trypanosomiasis, is a chronic parasitic disease caused by the flagellated protozoan Trypanosoma cruzi that affects about 8 million people around the world where more than 25 million are at risk of contracting the infection. Despite of being endemic on 21 Latin-American countries, Chagas disease has become a global concern due to migratory movements. Unfortunately, available drugs for the treatment have several limitations and they are generally administered during the chronic phase of the infection, when its efficacy is considered controversial. Thus, prophylactic and/or therapeutic vaccines are emerging as interesting control alternatives. In this work, we proposed Trypanosoma cruzi 80 kDa prolyl oligopeptidase (Tc80) as a new antigen for vaccine development against Chagas disease.Methodology/Principal findingsIn a murine model, we analyzed the immune response triggered by different immunization protocols based on Tc80 and evaluated their ability to confer protection against a challenge with the parasite. Immunized mice developed Tc80-specific antibodies which were able to carry out different functions such as: enzymatic inhibition, neutralization of parasite infection and complement-mediated lysis of trypomastigotes. Furthermore, vaccinated mice elicited strong cell-mediated immunity. Spleen cells from immunized mice proliferated and secreted Th1 cytokines (IL-2, IFN-γ and TNF-α) upon re-stimulation with rTc80. Moreover, we found Tc80-specific polyfunctional CD4 T cells, and cytotoxic T lymphocyte activity against one Tc80 MHC-I peptide.Immunization protocols conferred protection against a T. cruzi lethal challenge. Immunized groups showed a decreased parasitemia and higher survival rate compared with non-immunized control mice. Moreover, during the chronic phase of the infection, immunized mice presented: lower levels of myopathy-linked enzymes, parasite burden, electrocardiographic disorders and inflammatory cells.Conclusions/SignificanceConsidering that an early control of parasite burden and tissue damage might contribute to avoid the progression towards symptomatic forms of chronic Chagas disease, the efficacy of Tc80-based vaccines make this molecule a promising immunogen for a mono or multicomponent vaccine against T. cruzi infection.

Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi

“…Its data revealed an improved outcome on vaccinated animals, which suffered fewer alterations (QTc and PR interval prolongation), compared to Se/PBS infected mice. Similar alterations were previously observed in other T. cruzi-infected mice (6,49). Interestingly, between vaccinated groups, Sc/CDA presented the worst performance.…”

“…Mice were anesthetized (100 mg ketamine and 16 mg xylazine/kg mouse) at 120 dpi and heart electrical activity was recorded with a Temis TM-300-V electrocardiograph as previously reported (6). Corrected QT interval was calculated by the Bazett formula adapted for mouse (40).…”

“…Parasite burden in skeletal and heart muscle at 240 dpi was determined by a qPCR adapted from Cummings et al (41) as previously described (6). Parasite burden was expressed as parasite equivalent/50 ng of total DNA.…”

“…In order to analyze the protection conferred by each formulation, immunized female C3H mice were challenged with a lethal dose of the highly virulent RA strain of T. cruzi. This model of infection is well-established in our lab (6,16,36,43). The number of blood trypomastigotes, weight loss, and the survival rate were employed as endpoints for assessing vaccine performance.…”

Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

“…In our laboratory, we took advantage of attenuated Salmonella enterica serovar Typhimurium aroA that can be administered orally and is easily produced, facilitating its implementation in vaccination campaigns. We have previously demonstrated the efficacy of this transport system as prophylactic vaccines to T. cruzi infection ( 19 , 21 , 24 , 50 , 51 ). Based on these promising results, we have evaluated the therapeutic effect of Salmonella as a DNA delivery system of Cz upon the coadministration with GM-CSF as adjuvant with good performance ( 25 ).…”