Protective Immunity Against Trypanosoma cruzi Infection in a Highly Susceptible Mouse Strain After Vaccination with Genes Encoding the Amastigote Surface Protein-2 and Trans-Sialidase

Abstract

Protective immunity against lethal infection is developed when BALB/c or C57BL/6 mice are immunized with plasmids containing genes from the protozoan parasite Trypanosoma cruzi. However, genetic vaccination of the highly susceptible mouse strain A/Sn promoted limited survival after challenge. This observation questioned whether this type of vaccination would be appropriate for highly susceptible individuals. Here, we compared the protective efficacy and the immune response after individual or combined genetic vaccination of A/Sn mice with genes encoding trans-sialidase (TS) or the amastigote surface protein-2 (ASP-2). After challenge, a significant proportion of A/Sn mice immunized with either the asp-2 gene or simultaneously with asp-2 and ts genes, survived infection. In contrast, the vast majority of mice immunized with the ts gene or the vector alone died. Parasitological and histological studies performed in the surviving mice revealed that these mice harbored parasites; however, minimal inflammatory responses were seen in heart and striated muscle. We used this model to search for an in vitro correlation for protection. We found that protective immunity correlated with a higher secretion of interferon- by spleen cells on in vitro restimulation with ASP-2 and the presence of ASP-2-specific CD8 cells. Depletion of either CD4 or CD8 or both T-cell subpopulations prior to the challenge rendered the mice susceptible to infection demonstrating the critical contribution of both cell types in protective immunity. Our results reinforce the prophylactic potential of genetic vaccination with asp-2 and ts genes by describing protective immunity against lethal T. cruzi infection and chronic tissue pathology in a highly susceptible mouse strain.

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).…”

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).…”

“…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.…”

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.…”