The In Vivo Susceptibility of
            <i>Leishmania donovani</i>
            to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

Carter, K. C.; Sundar, Shyam; Spickett, Corinne M.; Pereira, Olga; Mullen, Alexander B.

doi:10.1128/aac.47.5.1529-1535.2003

Cited by 54 publications

(49 citation statements)

References 28 publications

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“…SSG, BSO-NIV, and BSO-NIV/SSG treatments were associated with an increase in host ␥-GCS in mice infected with either strain of L. donovani in the spleen but not in the liver. There is some correlation between host ␥-GCS expression and total liver GSH levels measured in previous studies (6). For example, SSG treatment had no significant effect on total liver GSH levels measured in mice infected with either L. donovani strain (6) or host ␥-GCS expression in this study.…”

Section: Discussionsupporting

confidence: 45%

“…Free GSH has a plasma half-life of 2 min and is rapidly removed from the circulation via the kidneys and lungs (26). We have previously shown that using a NIV formulation can alter drug pharmacokinetics and improve targeting to tissues (6). The antileishmanial activity of GSH was dependent on the environmental conditions and the strain of L. donovani used.…”

Section: Discussionmentioning

confidence: 99%

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

Carter

Hutchison

Henriquez

et al. 2006

Antimicrob Agents Chemother

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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.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 99%

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

Carter

Hutchison

Henriquez

et al. 2006

Antimicrob Agents Chemother

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“…Commercially obtained Golden Syrian hamsters (Mesocricetus auratus) were used for maintenance of L. donovani strains (Harlan Olac, Bicester, United Kingdom). L. donovani strain LV82 was used (13), and mice were infected on day 0 by intravenous injection (tail vein, no anesthetic) with 1 ϫ 10 7 to 2 ϫ 10 7 L. donovani amastigotes. Animal experiments were carried out in accordance with UK Home Office regulations.…”

Section: Methodsmentioning

confidence: 99%

Neutrophils Contribute to Development of a Protective Immune Response during Onset of Infection withLeishmania donovani

et al. 2008

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Neutrophils are key components of the inflammatory response and as such contribute to the killing of microorganisms. In addition, recent evidence suggests their involvement in the development of the immune response. The role of neutrophils during the first weeks post-infection with Leishmania donovani was investigated in this study. When L. donovani-infected mice were selectively depleted of neutrophils with the NIMP-R14 monoclonal antibody, a significant increase in parasite numbers was observed in the spleen and bone marrow and to a lesser extent in the liver. Increased susceptibility was associated with enhanced splenomegally, a delay in the maturation of hepatic granulomas, and a decrease in inducible nitric oxide synthase expression within granulomas. In the spleen, neutrophil depletion was associated with a significant increase in interleukin 4 (IL-4) and IL-10 levels and reduced gamma interferon secretion by CD4؉ and CD8 ؉ T cells. Increased production of serum IL-4 and IL-10 and higher levels of Leishmania-specific immunoglobulin G1 (IgG1) versus IgG2a revealed the preferential induction of Th2 responses in neutrophil-depleted mice. Altogether, these data suggest a critical role for neutrophils in the early protective response against L. donovani, both as effector cells involved in the killing of the parasites and as significant players influencing the development of a protective Th1 immune response.The best-characterized function of neutrophils or polymorphonuclear neutrophils is their preeminent role in the phagocytosis and killing of invading microorganisms via the generation of oxygen intermediates and the release of lytic enzymes stored in their granules. Neutrophils, by promoting tissue injury, also contribute to the initiation of inflammation, an essential step in the launching of immunity. In addition to their being key components of the inflammatory response, an immunoregulatory role for neutrophils during microbial infection has recently been identified via the secretion of cytokines and chemokines (reviewed in reference 16), which were shown to contribute to the recruitment and activation of antigen-presenting cells (APCs). Thus, neutrophils are now recognized as important decision shapers during the early phases of the immune response (reviewed in reference 45).The role of neutrophils in infections with Leishmania has been mainly studied using the murine model of cutaneous leishmaniasis induced by the subcutaneous injection of Leishmania major. Transient depletion of neutrophils prior to infection with L. major had a significant influence on the number of parasites surviving at the site of L. major inoculation in both resistant and susceptible mice. In strains of mice resistant to infection, such as C57BL/6 and C3H/HeJ, depletion of neutrophils by the injection of a monoclonal antibody (MAb) depleting either neutrophils (NIMP-R14) or both neutrophils and eosinophils (RB6-8C5) at the time of infection and/or during the first week of infection led to an increase in the parasite load at the site...

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“…In laboratory studies on Leishmania a series of sesquiterpenes have been shown to reverse drug resistance due to P-glycoproteins in an L. tropica clone (119). Another study suggested a strategy of inhibition of thiol levels by coadministration of antimony with an inhibitor of glutathione biosynthesis (30). It is, however, unlikely that these approaches will have any clinical relevance.…”

Section: ϫ7mentioning

confidence: 99%

Drug Resistance in Leishmaniasis

2006

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SUMMARY Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

Cited by 54 publications

References 28 publications

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

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

Neutrophils Contribute to Development of a Protective Immune Response during Onset of Infection withLeishmania donovani

Drug Resistance in Leishmaniasis

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