Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites

Abstract

Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of the mammalian hosts. In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae. We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes. The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG. Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae. In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages. The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae. We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania. However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling. In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity. In contrast, ARG activity was undetectable in mice inoculated with the non-pathogenic L. tarentolae. Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication. Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice. ARG activity can be used as one of the main marker of the disease severity.

The outcome of arginase activity inhibition in BALB/c mice hosting Leishmania tropica

“…8 Here, we used nor- and second, L. tropica creates a minor CL phenotype with a chronic course in BALB/c mice. 18,21 Following the prevention of ARG activity, the parasite burden declined in the dLNs of mice in nor-NOHA-Ltrop group in comparison with PBS-Ltrop group despite the fact that footpad size was not remarkably different between two groups. The ample evidence has represented that the footpad thickness is not a valid clinical measure of CL in mice.…”

“…The inhibitor was administered in minimal dose (10 μg/mouse) and distant time intervals (twice a week) to have a minimum effect to know whether this inhibitor can partially protect the Ltrop ‐infected mice through ARG activity modulation and raising the NO amount instead of urea. This study focused on L. tropica infection first because, BALB/c mice are not a susceptible animal model for L. tropica and second, L. tropica creates a minor CL phenotype with a chronic course in BALB/c mice …”

“…The amount of ARG in infected footpad was measured as previously described . Briefly, the footpads were homogenized in PBS and debris was eliminated by centrifugation in low speed 0.2 x g /10 min.…”

Herbal Drugs with Promising Anti-Leishmanial Activity: New Hope for Leishmaniasis Treatment

“…The disease is caused by various species of Leishmania parasites. Leishmaniasis is transmitted by biting of infected female sand flies (1,2). Leishmania has 2 forms, amastigotes and promastigotes.…”

“…Leishmaniasis is endemic in 98 countries and 350 million people are at the risk of infection. Leishmanicidals have to be controlled at low doses because frequently used drugs have severe side effects, and therefore drug resistance could appear rapidly (1)(2)(3)(4). About 90% of the CL occur in 8 countries, including Iran, Saudi Arabia, Iraq, Afghanistan, Algeria, Syria, Brazil, and Peru (2,5,6).…”