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, 72 (1), 46-53

Immunotherapy of Trypanosoma Cruzi Infection With DNA Vaccines in Mice

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Immunotherapy of Trypanosoma Cruzi Infection With DNA Vaccines in Mice

Eric Dumonteil et al. Infect Immun.

Abstract

The mechanisms involved in the pathology of chronic chagasic cardiomyopathy are still debated, and the controversy has interfered with the development of new treatments and vaccines. Because of the potential of DNA vaccines for immunotherapy of chronic and infectious diseases, we tested if DNA vaccines could control an ongoing Trypanosoma cruzi infection. BALB/c mice were infected with a lethal dose (5 x 10(4) parasites) as a model of acute infection, and then they were treated with two injections of 100 microg of plasmid DNA 1 week apart, beginning on day 5 postinfection. Control mice had high levels of parasitemia and mortality and severe cardiac inflammation, while mice treated with plasmid DNA encoding trypomastigote surface antigen 1 or Tc24 had reduced parasitemia and mild cardiac inflammation and >70% survived the infection. The efficacy of the immunotherapy also was significant when it was delayed until days 10 and 15 after infection. Parasitological analysis of cardiac tissue of surviving mice indicated that most mice still contained detectable parasite kinetoplast DNA but fewer mice contained live parasites, suggesting that there was efficient but not complete parasite elimination. DNA vaccine immunotherapy was also evaluated in CD1 mice infected with a low dose (5 x 10(2) parasites) as a model of chronic infection. Immunotherapy was initiated on day 70 postinfection and resulted in improved survival and reduced cardiac tissue inflammation. These results suggest that DNA vaccines have strong potential for the immunotherapy of T. cruzi infection and may provide new alternatives for the control of Chagas' disease.

Figures

FIG. 1.
FIG. 1.
Parasitemia and survival of BALB/c mice infected with a lethal dose of T. cruzi and treated with DNA vaccines. Mice were infected with 5 × 104 T. cruzi parasites (strain H4) and treated on days 5 and 12 (arrows) with intramuscular injections of 100 μg of plasmid DNA encoding TSA-1 (•) or Tc24 (▴), control pcDNA3 plasmid (○), or a saline solution (□). (A and B) Infection monitored by measuring parasitemia. The values are means ± standard errors of the means for 3 to 15 mice per group. (C) Survival of infected and treated BALB/c mice.
FIG. 2.
FIG. 2.
Histopathological analysis of cardiac tissue from BALB/c mice infected with a lethal dose of T. cruzi and treated with DNA vaccines. Cardiac tissue was examined on days 40 to 50 postinfection (A, B, C, E, and G) or on day 140 postinfection (D, F, and H). Infected mice treated with a saline solution (A) or the control pcDNA3 plasmid (B) died by days 40 to 45 and had extensive inflammatory infiltrates, scattered to abundant amastigote nests (arrows), and some fibrosis and necrosis. Mice treated with 100 μg of DNA vaccine encoding TSA-1 on days 5 and 12 (C) had only mild focal inflammation (asterisk). When treatment was delayed and administered on days 10 and 17 postinfection (E) or on days 15 and 22 postinfection (G), the inflammation level appeared to be intermediate between that of treated mice and that of untreated mice. On day 140 after infection, BALB/c mice treated with TSA-1 DNA on days 5 and 12 (D) or on days 10 and 17 (F), as well as mice treated with Tc24 DNA (H), all had very mild and diffuse inflammatory infiltrates, and amastigote nests were undetectable except in one mouse.
FIG. 3.
FIG. 3.
Parasitemia and survival of BALB/c mice infected with a lethal dose of T. cruzi and treated with DNA vaccines at different times. Mice were infected with 5 × 104 T. cruzi parasites (strain H4), and then they were treated on days 5 and 12 (•), on days 10 and 17 (▵), or on days 15 and 22 (▴) postinfection with intramuscular injections of 100 μg of plasmid DNA encoding TSA-1 or they were treated with a saline solution (□). (A) Infection monitored by measuring parasitemia. The values are means for 5 to 15 mice per group. (B) Survival of infected and treated BALB/c mice.
FIG. 4.
FIG. 4.
Histopathological analysis of cardiac tissue from CD1 mice infected with a low dose of T. cruzi and treated with DNA vaccines. (A and B) Mice were infected with 5 × 102 T. cruzi parasites, treated with an intramuscular injection of a saline solution (A) or with 100 μg of DNA vaccine encoding TSA-1 (B) during the chronic phase on days 70 and 77 postinfection, and sacrificed on day 140 postinfection. The cardiac tissue of control mice had extensive inflammatory infiltrates, while that of DNA-treated mice had only mild diffuse inflammation. (C) Uninfected control CD1 mice.

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