CD8⁺-T-Cell-Dependent Control ofTrypanosoma cruziInfection in a Highly Susceptible Mouse Strain after Immunization with Recombinant Proteins Based on Amastigote Surface Protein 2

Abstract

We previously described that DNA vaccination with the gene encoding amastigote surface protein 2 (ASP-2) protects approximately 65% of highly susceptible A/Sn mice against the lethal Trypanosoma cruzi infection. Here, we explored the possibility that bacterial recombinant proteins of ASP-2 could be used to improve the efficacy of vaccinations. Initially, we compared the protective efficacy of vaccination regimens using either a plasmid DNA, a recombinant protein, or both sequentially (DNA priming and protein boosting). Survival after the challenge was not statistically different among the three mouse groups and ranged from 53.5 to 75%. The fact that immunization with a recombinant protein alone induced protective immunity revealed the possibility that this strategy could be pursued for vaccination. We investigated this possibility by using six different recombinant proteins representing distinct portions of ASP-2. The vaccination of mice with glutathione S-transferase fusion proteins representing amino acids 261 to 500 or 261 to 380 of ASP-2 in the presence of the adjuvants alum and CpG oligodeoxynucleotide 1826 provided remarkable immunity, consistently protecting 100% of the A/Sn mice. Immunity was completely reversed by the in vivo depletion of CD8 ؉ T cells, but not CD4 ؉ T cells, and was associated with the presence of CD8 ؉ T cells specific for an epitope located between amino acids 320 and 327 of ASP-2. We concluded that a relatively simple formulation consisting of a recombinant protein with a selected portion of ASP-2, alum, and CpG oligodeoxynucleotide 1826 might be used to cross-prime strong CD8؉ -T-cell-dependent protective immunity against T. cruzi infection.

Swimming against the current: genetic vaccination against Trypanosoma cruzi infection in mice

“…Upon plasmid immunisation, depletion of either CD4 + or CD8 + T cells completely reversed protective immunity, thus demonstrating a non-overlapping role for these two subpopulations (Katae et al 2002, Vasconcelos et al 2004. Following vaccination with recombinant protein of ASP-2 in alum and CpG ODN, only depletion of CD8 + , but not CD4 + , T cells reversed protective immunity (Araújo et al 2005). Finally, by using a single T. cruzi epitope recognised by CD8 + T cells, Miyahira et al (2005) elicited a protective immune response using a heterologous prime-boost strategy with recombinant adenovirus and vaccinia virus.…”

“…To determine the role of immunisation in reducing chronic phase disease symptoms, a number of experiments using different animal models must be performed. In many of the models described above, tissue inflammation and parasitism in the late chronic phase were significantly reduced following prophylactic vaccination (Garg & Tarleton 2002, Vasconcelos et al 2004, Araújo et al 2005. Therefore it is possible that prophylactic vaccinations indeed halt the development of the chronic phase immunopathologies.…”

Infection with Trypanosoma cruzi Restricts the Repertoire of Parasite-Specific CD8+ T Cells Leading to Immunodominance

“…Such a strong immune response did not cause any discernible immunopathology. It in fact led to a reduced parasite development and prevented the establishment of chronic phase tissue pathologies (46,47). Also, some of these vaccinated mice completely cleared the parasite and established sterile immunity (46,47).…”

Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

“…Under these circumstances, we obtained reduced parasitism and limited disease development. Also, in some cases, we reached sterile protection against T. cruzi, showing that vaccination could be a useful approach to boost the host immunodominant response (9)(10)(11)(12). We concluded that aberrantly high immunodominant responses may, in some cases, clear the parasite from the host.…”

“…Based on that assumption, the means to break the deadlock is through increasing and/or broadening the immune responses prior to and/or during infection (9)(10)(11). Whether immunotherapy should focus on dominant, subdominant, or cryptic epitopes or on all of them at the same time can be addressed experimentally in the near future and may provide the basis for rational interventions.…”