Sodium stibogluconate resistance in Leishmania donovani correlates with greater tolerance to macrophage antileishmanial responses and trivalent antimony therapy

Carter, K. C.; Hutchison, Sharon; Boitelle, A.; Murray, Henry W.; Sundar, Shyam; Mullen, Alexander B.

doi:10.1017/s0031182005008486

Cited by 26 publications

(33 citation statements)

References 23 publications

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“…L. donovani-specific immunoglobulin G1 (IgG1) and IgG2a levels were determined as previously described, using serum harvested at the termination of the experiment (12).…”

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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“…L. donovani-specific immunoglobulin G1 (IgG1) and IgG2a levels were determined as previously described, using serum harvested at the termination of the experiment (12).…”

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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“…Age-and sex-matched BALB/c mice (20 to 25 g, males or females) in-house bred at Strathclyde University were used in this study. Commercially obtained Golden Syrian hamsters (Mesocricetus auratus; Harlan Olac, Bicester, United Kingdom) were used for maintenance of the two L. donovani parasite strains used (strains 200011, SSG-R, and 200016, SSG susceptible [SSG-S]) (7). Mice were infected by intravenous injection (tail vein, no anesthetic) with 1 ϫ 10 7 to 2 ϫ 10 7 L. donovani amastigotes on day 0 (5), and studies were carried out in accordance with United Kingdom Home Office regulations.…”

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confidence: 99%

“…Macrophages studies were carried out as described by Carter et al (7). L. donovani-infected cells were treated with complete medium (controls) or complete medium containing GSH (2.5 to 20 mM), SSG (0.575 mM Sb v ), GSH and SSG (2.5 mM GSH, 0.575 mM Sb v ), GSH alone (0.05 to 15 mM), IFN-␥-lipopolysaccharide (LPS) alone (0.01 to 100 U IFN-␥/ml, 0.01 to 100 ng/ml LPS), or GSH and IFN-␥-LPS (50 to 500 M GSH, 0.01 to 100 U IFN-␥/ml, 0.01 to 100 ng/ml LPS).…”

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confidence: 99%

“…The percentages of CD3 ϩ , CD45R/B220 ϩ , and F4/80 ϩ cells present in the spleens of control and treated mice were determined by flow cytometry as described by Carter et al (7). Cells were analyzed using a FACS Canto (BD Systems), gating on forward and side scatter, and the FACsDiva software was used to analyze data.…”

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confidence: 99%

“…Single-cell suspensions, prepared from the spleens of uninfected and infected mice, were used in proliferation assays and incubated with medium alone (unstimulated controls) or concanavalin A (5 g/ml; stimulated controls) as described by Carter et al (7). Cell supernatants were stored at Ϫ20°C until nitrite and cytokine determination could be performed.…”

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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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STAT4 is critical for immunity but not for antileishmanial activity of antimonials in experimental visceral leishmaniasis

et al. 2013

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Summary We and others have previously shown that IL-12 is indispensable for immunity and is required for optimal antiparasitic activity of antimonials in experimental visceral leishmaniasis caused by Leishmania donovani. In this study we investigated the role of STAT4 in immunity against L. donovani using STAT4 knockout mice and also determined the effect of STAT4 deficiency in response to antimonial therapy. Upon infection with L. donovani, stat4−/− BALB/c and C57BL/6 mice showed enhanced susceptibility to Leishmania during late time points of infection which was associated with a marked reduction in Th1 responses and hepatic immunopathology. Interestingly, these defects in Th1 responses in stat4−/− did not impair the antimonial chemotherapy as both stat4−/− and WT mice showed comparable levels of parasite clearance from the liver and spleen. These findings highlight the role of STAT4 in immunity to L. donovani infection and also provide evidence that STAT4 is dispensable for antimonial based chemotherapy.

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Sodium stibogluconate resistance in Leishmania donovani correlates with greater tolerance to macrophage antileishmanial responses and trivalent antimony therapy

Cited by 26 publications

References 23 publications

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

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

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

STAT4 is critical for immunity but not for antileishmanial activity of antimonials in experimental visceral leishmaniasis

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