Resistance of leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase

K.C. Carter, S. Hutchison, F.L. Henriquez, M. Legare, M. Ouellette, C.W. Roberts, A. Mullen

Research output: Contribution to journalArticle

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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.
LanguageEnglish
Pages88-95
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume50
Issue number1
DOIs
Publication statusPublished - Jan 2006

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Antimony Sodium Gluconate
Glutamate-Cysteine Ligase
Leishmania donovani
Parasites
gamma-glutamylcysteine
Macrophages
Antimony
Poisons

Keywords

  • leishmania donovani
  • chemotherapy

Cite this

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title = "Resistance of leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-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.",
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author = "K.C. Carter and S. Hutchison and F.L. Henriquez and M. Legare and M. Ouellette and C.W. Roberts and A. Mullen",
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Resistance of leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase. / Carter, K.C.; Hutchison, S.; Henriquez, F.L.; Legare, M.; Ouellette, M.; Roberts, C.W.; Mullen, A.

In: Antimicrobial Agents and Chemotherapy, Vol. 50, No. 1, 01.2006, p. 88-95.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Resistance of leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase

AU - Carter, K.C.

AU - Hutchison, S.

AU - Henriquez, F.L.

AU - Legare, M.

AU - Ouellette, M.

AU - Roberts, C.W.

AU - Mullen, A.

PY - 2006/1

Y1 - 2006/1

N2 - 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.

AB - 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.

KW - leishmania donovani

KW - chemotherapy

U2 - 10.1128/AAC.50.1.88-95.2006

DO - 10.1128/AAC.50.1.88-95.2006

M3 - Article

VL - 50

SP - 88

EP - 95

JO - Antimicrobial Agents and Chemotherapy

T2 - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 1

ER -