Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

Murray, Henry W.

doi:10.1128/aac.45.8.2185-2197.2001

Cited by 200 publications

(211 citation statements)

References 189 publications

(290 reference statements)

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“…However, current chemotherapeutic agents are unsuitable, in part because of their high toxicity and the emergence of drug resistance (4,5). Thus, identification of novel immunological targets that can be effective against both antimony-susceptible and -resistant strains of Leishmania is of tremendous economic and medical importance (6).…”

Section: Ubiquitin Conjugation Of Open Reading Frame F Dna Vaccine Lementioning

confidence: 99%

“…In the case of GE1F8R-infected and pUMVC3The culture supernatant was collected and analyzed for their nitrite content using Griess reagent containing 1% sulfanilamide in 5% H 3 PO 4 and an aqueous solution of N-1-naphthylethylenediamine dihydrochloride. Griess reagent was added to the culture supernatant at ratio of 1:1 and incubated for 15 min at 37°C in the dark.…”

Section: Quantification Of Nomentioning

confidence: 99%

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Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Sharma

Madhubala

2009

The Journal of Immunology

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Resistance of Leishmania donovani to sodium antimony gluconate has become a critical issue in the current, prolonged epidemic in India. Hence, there is an urgent need for a vaccine that is protective against both antimony-susceptible and -resistant strains of L. donovani. The multigene LD1 locus located on chromosome 35 of Leishmania is amplified in ∼15% of the isolates examined. The open reading frame F (ORFF), a potential vaccine candidate against visceral leishmaniasis, is part of the multigene LD1 locus. ORFF was expressed as a chimeric conjugate of ubiquitin to elicit an Ag-specific cell-mediated immune response. Analysis of the cellular immune responses of ubiquitin-conjugated ORFF (UBQ-ORFF) DNA-immunized, uninfected BALB/c mice demonstrated that the vaccine induced enhanced IFN-γ-producing CD4+ and CD8+ T cells compared with nonubiquitinated ORFF DNA vaccine. Higher levels of IL-12 and IFN-γ and the low levels of IL-4 and IL-10 further indicated that the immune responses with UBQ-ORFF were mediated toward the Th1 rather than Th2 type. Infection of immunized mice with either the antimony-susceptible (AG83) or -resistant (GE1F8R) L. donovani strain showed that UBQ-ORFF DNA vaccine induced higher protection when compared with ORFF DNA. UBQ-ORFF DNA-immunized and -infected mice showed a significant increase in IL-12 and IFN-γ and significant down-regulation of IL-10. High levels of production of nitrite and superoxide, two macrophage-derived oxidants that are critical in controlling Leishmania infection, were observed in protected mice. The feasibility of using ubiquitinated-conjugated ORFF DNA vaccine as a promising immune enhancer for vaccination against both antimony-susceptible and -resistant strains of L. donovani is reported.

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Section: Ubiquitin Conjugation Of Open Reading Frame F Dna Vaccine Lementioning

confidence: 99%

Section: Quantification Of Nomentioning

confidence: 99%

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Sharma

Madhubala

2009

The Journal of Immunology

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“…To address this question, a well characterized axenic amastigote cell line (LdBOB) was used to investigate the effects of Sb V on intracellular thiol levels of isolated amastigotes (25). Initially, the sensitivity of LdBOB amastigotes and promastigotes for Sb was established by determining IC 50 values for both Sb III and Sb V (Fig. 5A).…”

Section: Effects Of Pentavalent Antimony On the Thiol Metabolism Of Lmentioning

confidence: 99%

“…Sb V was selectively toxic for the amastigote stage of Leishmania with an IC 50 of 200 g ml Ϫ1 , whereas LdBOB promastigotes were totally insensitive to Sb V concentrations up to 1000 g ml Ϫ1 . To assess the effects of Sb V on intracellular thiols, mid-log axenic amastigotes were incubated with 600 g ml Ϫ1 Sb V (3ϫ IC 50 ), and thiols were analyzed over a 24-h period. The levels of both T[SH] 2 and GSH fell steadily throughout the incubation with Sb V (Fig.…”

Section: Effects Of Pentavalent Antimony On the Thiol Metabolism Of Lmentioning

confidence: 99%

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Wyllie

Cunningham

Fairlamb

2004

Journal of Biological Chemistry

264

244

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Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb III ) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb III decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb III inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.Leishmania parasites cause a wide spectrum of human and animal infections ranging from life-threatening visceral disease to disfiguring mucosal and cutaneous forms of the disease. These "neglected" diseases are a significant cause of morbidity and mortality in 88 countries in the Americas, Africa, Asia, and Southern Europe; millions of people are at risk, and 400,000 new cases are reported annually (1). Leishmania spp. are obligate intracellular parasites of the vertebrate reticuloendothelial system, where they multiply as amastigotes in macrophage phagolysosomes; transmission is by blood-sucking sandflies, in which they proliferate as extracellular promastigotes. Treatment of the leishmaniases is far from ideal, and pentavalent antimonial (Sb V ) 1 preparations such as sodium stibogluconate (Pentostam) have been the front-line drugs for more than half a century. However, the clinical value of antimony therapy is now threatened because of the emergence of drug resistance (2) and co-infection with human immunodeficiency virus (3). Sb V is generally regarded as a pro-drug that first has to be activated by conversion to the trivalent form (Sb III ) (4). However, the site of reduction (host macrophage, amastigote, or both) and the mechanism of reduction (enzymatic or nonenzymatic) remain unclear (4 -8). The mode of action of these drugs is poorly understood. Sb III reversibly inhibits trypanothione reductase in vitro (9), but this has not been demonstrated in the intact parasite. However, inhibition of this unique and essential enzyme (10 -12) is of particular interest, because trypanothione (N 1 ,N 8Ϫ bis(glutathionyl) spermidine (T[SH] 2 )) is a key intermediate in the regulation of thiol redox homeostasis, as well as in defense against chemical (13,14) and oxidative stress (15, 16).Paradoxically, more is known about the mechanism of resistance to Sb III than its mode of action (17). A considerable body of evidence implicates trypanothione a...

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“…The structure and function of this host organelle are reported to be highly affected by the parasitic attack. The pentavalent antimonial compound SAG are widely used as first-line chemotherapeutic 165,166 agents against all forms of leishmaniasis including visceral leishmaniasis 167,168 . In this work, we have assessed the status of host liver peroxisomes after the complete treatment of the L. donovani infected animals with standard dose of SAG.…”

Section: Discussionmentioning

confidence: 99%

Repair of Impaired Host Peroxisomal Properties Cropped Up Due to Visceral Leishmaniasis May Lead to Overcome Peroxisome Related Genetic Disorder Which May Develop Later After Treatment

Datta¹,

Gupta²,

Raychaudhury³

2011

Advances in the Study of Genetic Disorders

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Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

Cited by 200 publications

References 189 publications

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Repair of Impaired Host Peroxisomal Properties Cropped Up Due to Visceral Leishmaniasis May Lead to Overcome Peroxisome Related Genetic Disorder Which May Develop Later After Treatment

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