Studies in humans and in experimental models suggest the involvement of the immune system for efficacy of drug treatment against protozoan parasites. This study tested this hypothesis by using various cytokine and inducible nitric oxide synthase (iNOS) knockout (KO) mice infected with Trypanosoma cruzi and treated with benznidazole. In contrast with the 100% parasitologic cure rate achieved in wild-type animals, benznidazole failed to cure 100%, 42%, 35%, and 28% of interferon-gamma, interleukin-12 (protein 40), protein 55-tumor necrosis factor receptor, and iNOS KO mice, respectively. These results suggest that activation of the immune system by the parasite and endogenous interferon-gamma play a major role in the efficacy of benznidazole against infection with T. cruzi.
We investigated the influence of CD4؉ T lymphocytes, CD8 ؉ T lymphocytes, and B lymphocytes on the efficacy of posaconazole (POS) and the reference drug benznidazole (BZ) during treatment of acute Trypanosoma cruzi infection in a murine model. Wild-type mice infected with T. cruzi and treated with POS or BZ presented no parasitemia, 100% survival, and 86 to 89% cure rates, defined as the percentages of animals with negative hemocultures at the end of the observation period. CD4؉ -T-lymphocyte-knockout (KO) mice infected with T. cruzi and treated with BZ or POS controlled parasitemia during treatment, although circulating parasites reappeared after drug pressure cessation, leading to only a 6% survival rate and no cure. CD8؉ -Tlymphocyte-KO mice infected with T. cruzi and treated with POS or BZ had intermediate results, displaying discrete parasitemia after the treatment was ended, 81 and 86% survival, and cure rates of 31 and 66%, respectively. B-lymphocyte-KO mice infected with T. cruzi and treated with BZ relapsed with parasitemia 1 week after the end of treatment and had a 67% survival rate and only a 22% cure rate. In contrast, the activity of POS was much less affected in these animals, with permanent suppression of parasitemia, 100% survival, and a 71% cure rate. Our results demonstrate that abrogation of different lymphocytes' activities has distinct effects on the efficacy of POS and BZ in this experimental model, probably reflecting different parasite stages preferentially targeted by the two drugs and distinct cooperation patterns with the host immune system.
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