Abstract
Glucantime (SbV) is the first-line treatment against American Tegumentary Leishmaniasis. Resistance cases to this drug have been reported and related to host characteristics and parasite phenotypes. In this study, 12 Leishmania (Viannia) braziliensis isolates from patients that presented clinical cure (Responders—R) and relapse or therapeutic failure (Non-responders—NR) after treatment with antimony, were analyzed. These parasites were assessed by in vitro susceptibility to SbIII and SbV, serine proteases activity measured with substrate (z-FR-AMC) and specific inhibitors (TLCK, AEBSF and PMSF). In vitro susceptibility of axenic amastigotes to SbIII showed a significant difference between R and NR groups. The protease assays showed that TLCK inhibited almost 100% of activity in both axenic amastigotes and promastigotes while AEBSF inhibited around 70%, and PMSF showed lower inhibition of some isolates. Principal component and clustering analysis performed with these data yielded one homogeneous cluster with only NR isolates and three heterogeneous clusters with R and NR isolates. Additionally, differential expression of subtilisins (LbrM.13.0860 and LbrM.28.2570) and TXNPx (LbrM.15.1080) was evaluated in promastigotes and axenic amastigotes from both groups. The results showed a higher expression of LbrM.13.0860 and LbrM.15.1080 genes in axenic amastigotes, while LbrM.28.2570 gene had the lowest expression in all isolates, regardless of the parasite form. The data presented here show a phenotypic heterogeneity among the parasites, suggesting that exploration of in vitro phenotypes based on SbIII and serine proteases profiles can aid in the characterization of L. (V.) braziliensis clinical isolates.
Highlights
Glucantime (SbV) is the first-line treatment against American Tegumentary Leishmaniasis
In the American continent, Leishmania mexicana complex and subgenus Viannia species cause cutaneous and mucocutaneous forms that can develop into localized, disseminated or diffuse lesions, which is known as American Tegumentary leishmaniasis (ATL)[3]
The results showed a significant difference between the axenic amastigotes grouped as R and NR exposed to SbIII (p < 0.05, Fig. 1C)
Summary
Glucantime (SbV) is the first-line treatment against American Tegumentary Leishmaniasis Resistance cases to this drug have been reported and related to host characteristics and parasite phenotypes. 12 Leishmania (Viannia) braziliensis isolates from patients that presented clinical cure (Responders—R) and relapse or therapeutic failure (Non-responders—NR) after treatment with antimony, were analyzed. These parasites were assessed by in vitro susceptibility to SbIII and SbV, serine proteases activity measured with substrate (z-FR-AMC) and specific inhibitors (TLCK, AEBSF and PMSF). Trypanothione synthetase (TryS), trypanothione reductase (TR) and tryparedoxin (TXN) and tryparedoxin peroxidase (TXNPx)[11] This system is involved in the detoxification of metal ions, including reduction of SbV to SbIII, within the macrophage phagolysosome[8,10]. Increased abundance of TXNPx has been correlated with an enhanced thiol redox potential in antimony resistant parasites, in lab-generated s trains[15] and in clinical isolates[16]
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