Absence of CD4⁺T Lymphocytes, CD8⁺T Lymphocytes, or B Lymphocytes Has Different Effects on the Efficacy of Posaconazole and Benznidazole in Treatment of Experimental AcuteTrypanosoma cruziInfection

Abstract

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.

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…Several factors could be in play. A majority of studies that previously reported successful clearance of murine T. cruzi infections by posaconazole employed mice in early acute phase, with treatment starting as early as 1 day after the infection (8,9,33,34,37,38). It is possible that T. cruzi parasites in longer-term infections respond differently to treatment with posaconazole than parasites in early acute infections.…”

“…In that study, treatment failure was not evaluated by using an immunosuppression protocol, and it is possible that the sensitivity of parasite detection in that study was lower than in the current study. Failure to perform immunosuppression after the treatment also limits the sensitivity of three other studies from this list (33,34,38).…”

Ergosterol biosynthesis and drug development for Chagas disease

“…Other studies have demonstrated that the anti-T. cruzi activity of POS in a murine model of acute Chagas disease is much less dependent on interferon-γ than that of BZN (Ferraz et al 2007). It has also been shown that ablation of TCD4 + , TCD8 + and B lymphocytes has distinct effects on POS and BZN activity in the same experimental model (Ferraz et al 2009). POS efficacy was especially dependent on the presence of functional TCD8 + cells, but relatively insensitive to the absence of LB cells, yet the reverse was true for BZN; the activity of both drugs was markedly reduced in the absence of TCD4 + cells.…”

“…POS efficacy was especially dependent on the presence of functional TCD8 + cells, but relatively insensitive to the absence of LB cells, yet the reverse was true for BZN; the activity of both drugs was markedly reduced in the absence of TCD4 + cells. These results were interpreted in terms of the different parasite stages preferentially targeted by the two drugs (intracellular amastigotes by POS, extracellular trypomastigotes by BZN) and distinct cooperation patterns with the host's immune system (Ferraz et al 2009). An independent study in a similar experimental model found that POS was more effective than BZN in preventing heart damage and promoting a trypanocidal immune response (Olivieri et al, unpublished observations).…”

Avaliação das perspectivas terapêuticas do ácido L-tiazolidina-4-carboxílico, um análogo de prolina, na infecção de camundongos pelo Trypanosoma cruzi.

“…O Nifurtimox é produzido pela Bayer para tratamento da doença de Chagas em alguns países da América Latina e, além disso, para tratamento da tripanossomíase africana Gambiense no continente africano (Jannin e Villa, 2007). A ação antiparasitária do nifurtimox está associada à geração de espécies reativas de oxigênio (EROs), tais como ânion superóxido e peróxido de hidrogênio (Docampo, 1990;Maya et al, 2007;Dias et al, 2009) (Urbina et al, 1998;Ferraz et al, 2007Ferraz et al, , 2009) e o ravuconazol (Urbina e Docampo, 2003;Diniz Lde et al, 2010) dos quais são os candidatos mais avançados para o desenvolvimento da nova droga anti -T. cruzi, partindo para ensaios clínicos dentro de pouco tempo (Urbina, 2010). Compostos que inibem a enzima cisteína protease, ou mais precisamente, a cruzipaína, também são canditados para o desenvolvimento de quimioterapias.…”