Resistance ofLeishmania donovanito Sodium Stibogluconate Is Related to the Expression of Host and Parasite γ-Glutamylcysteine Synthetase

Abstract

Sequencing studies showed that the ␥-glutamylcysteine synthetase (␥-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant (SSG-R) and SSG-susceptible (SSG-S) Leishmania donovani strains were identical, indicating that SSG resistance was related to quantitative differences in ␥-GCS expression rather than gene interstrain polymorphisms. In vitro infection of murine macrophages with the SSG-R strain, but not the SSG-S strain, down regulated expression of host ␥-GCS, which would result in a reduction in intramacrophage glutathione (GSH) levels and promote an oxidative intramacrophage environment. This would inhibit, or minimize, the reduction of SSG pentavalent antimony to its more toxic trivalent form. Macrophage studies showed that the SSG-R strain expressed higher levels of ␥-GCS compared to the SSG-S strain, which would result in higher GSH levels, giving increased protection against oxidative stress and facilitating SSG efflux. However a similar differential effect on host and parasite ␥-GCS expression was not obtained when using tissues from infected mice. In this case ␥-GCS expression was organ and strain dependent for both the host and the parasite, indicating that environmental conditions have a profound effect on ␥-GCS expression. Consistent with the proposed mechanism from in vitro studies, increasing tissue GSH levels in the presence of SSG by cotreatment of L. donovani-infected mice with SSG solution and GSH incorporated into nonionic surfactant vesicles was more effective in reducing liver, spleen, and bone marrow parasite burdens than monotherapy with SSG. Together, these results indicate that SSG resistance is associated with manipulation of both host and parasite GSH levels by L. donovani.

Leishmania antimony resistance: what we know what we can learn from the field

“…Therefore, the in vivo chemotherapeutic outcome of antimonial therapy depends on the susceptibility of the parasite not only to the antimonial compound but also to other host-derived microbicidal molecules. Likewise, during treatment, the outcome of pentavalent antimonial therapy in vivo correlates with tolerance towards macrophage-derived microbicidal factors (Carter et al 2005;Carter et al 2006). The acquisition of drug resistance by Leishmania markedly alters the response of the host immune system following parasitic infection (Haldar et al 2010).…”

Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility

“…Our group and others have shown that the interaction between Leishmania and the human host extends beyond modulation of immunological functions to determinants of pharmacological responses [19-24]. L. (V.) panamensis infection of primary human macrophages and exposure to meglumine antimoniate (MA) or miltefosine modulate the expression of host cell ABC transporters and Solute Liquid Carriers (SLC), metabolic enzymes and scavenging molecules, differentially regulating the antileishmanial effect of these drugs [19, 20].…”

“…L. (V.) panamensis infection of primary human macrophages and exposure to meglumine antimoniate (MA) or miltefosine modulate the expression of host cell ABC transporters and Solute Liquid Carriers (SLC), metabolic enzymes and scavenging molecules, differentially regulating the antileishmanial effect of these drugs [19, 20]. Sb-resistant L donovani strains have been shown to induce expression of macrophage ABC transporters P-glycoprotein (P-gp), Multidrug resistance associated protein–1 (MRP-1) [21] and repression of macrophage gamma-glutamylcysteine synthetase (γ-GCS) [24], resulting respectively in reduced antimony accumulation and limited reduction to SbI II in cells infected with Sb-resistant parasites. These findings lend support to the concept that drug resistance in Leishmania can be conferred by a multiplicity of redundant mechanisms dependent both on the parasite and the host.…”

Modulation of Gene Expression in Human Macrophages Treated with the Anti- Leishmania Pentavalent Antimonial Drug Sodium Stibogluconate

“…It has been shown that an increase in GCLM expression could lead to an increase of GSH (8). Indeed, GSH reduces SbV to SbIII nonenzymatically (37), and the activity of SbV was associated with the manipulation of both host and parasite GSH levels by the parasite (6). Thiol levels are known to be important for the parasite itself, where SbIII decreases the level of intracellular GSH (21,43), and an increased level of thiols is associated with resistance to antimonials (15,22,24).…”