Abstract
BackgroundArginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection.Methodology/Principal findingsThe transcriptomic profiling identified a family of oxidoreductases in L. (L.) amazonensis wild-type (La-WT) and L. (L.) amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. We highlighted the identification of an oxidoreductase that could act as nitric oxide synthase-like (NOS-like), due to the following evidences: conserved domain composition, the participation of NO production during the time course of promastigotes growth and during the axenic amastigotes differentiation, regulation dependence on arginase activity, as well as reduction of NO amount through the NOS activity inhibition. NO quantification was measured by DAF-FM labeling analysis in a flow cytometry.Conclusions/SignificanceWe described an arginase-dependent NOS-like activity in L. (L.) amazonensis and its role in the parasite growth. The increased detection of NO production in the mid-stationary and late-stationary growth phases of La-WT promastigotes could suggest that this production is an important factor to metacyclogenesis triggering. On the other hand, La-arg- showed an earlier increase in NO production compared to La-WT, suggesting that NO production can be arginase-dependent. Interestingly, La-WT and La-arg- axenic amastigotes produced higher levels of NO than those observed in promastigotes. As a conclusion, our work suggested that NOS-like is expressed in Leishmania in the stationary growth phase promastigotes and amastigotes, and could be correlated to metacyclogenesis and amastigotes growth in a dependent way to the internal pool of L-arginine and arginase activity.
Highlights
Leishmaniasis is an important neglected tropical disease caused by the protozoa from Leishmania genus [1,2]
This parasite has a dimorphic life cycle: the procyclic promastigote form can be found in the mid-gut of the phlebotomine sand fly; the metacyclic promastigote can be found in the insect foregut and stomodeal valve and corresponds to the infective form; and the amastigote form can be found into macrophages of the mammalian host [3,4]
The oxidoreductase synthase-like (LmxM.19.1450/ EC 1.14.13.39) was identified and appeared up-regulated in La-arg- promastigotes when compared with La-WT promastigotes and in La-WT axenic amastigotes when compared with La-WT promastigotes, with foldchange 1.38 and 1.26, respectively
Summary
Leishmaniasis is an important neglected tropical disease caused by the protozoa from Leishmania genus [1,2]. (L.) amazonensis can generate cutaneous and/or diffuse cutaneous manifestations [1,2] This parasite has a dimorphic life cycle: the procyclic promastigote form can be found in the mid-gut of the phlebotomine sand fly; the metacyclic promastigote can be found in the insect foregut and stomodeal valve and corresponds to the infective form; and the amastigote form can be found into macrophages of the mammalian host [3,4]. The availability of L-arginine and arginase activity is essential for the survival of Leishmania inside both invertebrate and mammalian hosts [9,10,11,12]. Arginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite This competition can define the fate of Leishmania infection.
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