Effects of artesunate against Trypanosma cruzi.

Therapy against Trypanosma cruzi relies on only two chemically related nitro-derivative drugs, benznidazole and nifurtimox, both limited by poor efficacy and toxicity. It is suspected that with prolonged usage of these drugs, resistant parasites will be selected, which results in risk for treatment failure over the time. Herein, we studied the in vitro activity of artesunate, the most effective drug to treat severe P. falciparum and chloroquine-resistant P. vivax, on three strains of T. cruzi originated in different regions of Latin America (Argentina, Nicaragua and Brazil). The results of these assays showed that artesunate inhibits multiplication of epimastigotes (IC50 = 50, 6.10 and 23 µM, respectively) and intracellular amastigotes (IC50 = 15, 0.12 and 6.90 µM, respectively), indicating that it represents a potent anti-T. cruzi compound in terms of inhibiting parasite multiplication in vitro. We then tested the effect of artesunate in Balb/c mice infected with Brazil strain and found that it failed to cure the infection, suggesting that the drug may be unsuitable for in vivo treatment. When infected mice were treated with high doses AS + BZ, the outcome of infection was similar to that observed in mice treated with BZ alone. Nevertheless, understanding of structure-activity relationship of artesunate might lead to the development of new and effective drugs against T. cruzi.

Chronic human infection with Trypanosoma cruzi drives CD4+ T cells to immune senescence.

Previously we found that the frequency of IFN-gamma-producing CD8(+) T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease along with low levels of IL-2-secreting CD8(+) T cells in all clinical stages. This impairment of the parasite-specific T cell responses was associated with phenotypic features of immune senescence of the CD8(+) T cell compartment. These data prompted us to address the question of whether the CD4(+) T cell compartment also experiences signs of exhaustion. Thus, we performed a functional and phenotypical characterization of T. cruzi-specific and overall CD4(+) T cells in chronically infected subjects with different degrees of cardiac dysfunction. The results show an inverse association between disease severity and the frequency of T. cruzi-specific IFN-gamma-producing CD4(+) T cells. The high expression of CD27 and CD28 with a relative low expression of CD57 found on CD4(+)IFN-gamma(+) T cells suggests that the effector T cell pool in chronic T. cruzi infection includes a high proportion of newly recruited T cells, but a low frequency of long-term memory cells. The total CD4(+) T cell compartment shows signs of senescence and later stages of differentiation associated with more severe stages of the disease. These findings support the hypothesis that long-term T. cruzi infection in humans might exhaust long-lived memory T cells.

Assessment of CD8(+) T cell differentiation in Trypanosoma cruzi-infected children.

We previously reported that the T cell compartment in chronically Trypanosoma cruzi-infected adult subjects display functional and phenotypic signs of immune senescence. This study aimed to investigate the differentiation and the senescent profile of the overall CD8(+) T cell compartment in T. cruzi-infected children at the early stage of the disease. We found a lower percentage of naive (CD27(+)CD28(+)CD45RA(+)) and early antigen-experienced (CD45RA(-)CD27(+)CD28(+)), and higher percentages of late differentiated antigen-experienced (CD45RA(-)CD27(-)CD28(-)) CD8(+) T cells in T. cruzi-infected children as compared with age-matched uninfected controls. The expression of the interleukin (IL)-7R is also decreased on naive and on antigen-experienced total CD8(+) T cells with various degrees of differentiation. Conversely, the expression of HLA-DR, caspase-3, and CD57 did not vary on the total CD8(+) T cell compartment. These findings suggest that the duration of the infection is relevant in the process of immune senescent that this parasite can induce.