Role of Cytosolic Glyceraldehyde-3-Phosphate Dehydrogenase in Visceral Organ Infection by Leishmania donovani

Zhang, Wen-Wei; McCall, Laura-Isobel; Matlashewski, Greg

doi:10.1128/ec.00263-12

Cited by 26 publications

(21 citation statements)

References 54 publications

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“…(Ogungbe and Setzer, 2013), which is also involved in the glycosomal and cytosolic glycolytic pathways of Leishmania (Zhang, et al, 2013). One of these pathways involves NADH that is produced by GPDH, which can be evaluated using the XTT assay TrEO at 5 µg/mL promoted 3.2% haemolysis in human erythrocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Antileishmanial activity of essential oil and 6,7-dehydroroyleanone isolated from Tetradenia riparia

Demarchi

Thomazella

Terron

et al. 2015

Experimental Parasitology

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Tetradenia riparia plant is used as a traditional medicine in Africa for the treatment of inflammatory and infectious diseases as like parasitic. Therapy for leishmaniasis caused by Leishmania (Leishmania) amazonensis specie often fails, and the conventional drugs are toxic, expensive, require a long period of treatment, and adverse effects are common. The alternative therapies using natural products are inexpensive and have few or any adverse reaction. These reasons are sufficient to investigate the new natural therapeutic for leishmaniasis. We evaluated the potential of the essential oil (TrEO) and 6,7-dehydroroyleanone (TrROY) isolated from T. riparia on L. (L.) amazonensis promastigote and amastigote forms, cytotoxicity on human erythrocytes and murine macrophages, nitric production and inducible nitric oxide synthase (iNOS) mRNA expression. TrEO was the most effective to promote the Leishmania promastigote death. After 72 h incubation, the lethal dose of TrEO and TrROY that promoted 50% Leishmania death (LD50) were 0.8 μg/mL and 3 μg/mL, respectively. TrEO and TrROY were not cytotoxic to human erythrocytes, but TrROY was toxic to murine macrophages resulting in a low selectivity index. The transmission electronic microscopy showed that TrEO (0.03 μg/mL) was able to modify the promastigote ultrastructures suggesting autophagy as chromatin condensation, blebbing, membranous profiles and nuclear fragmentation. Infected-macrophages treated with TrEO (0.03 μg/mL) or TrROY (10 μg/mL) had an infection index decreased in 65 and 48%. TrEO did not induce iNOS mRNA expression or nitrite production in macrophages infected with Leishmania. TrROY and mainly TrEO promoted the Leishmania death, and TrROY showed loss toxicity to erythrocytes cells. Other compounds derived from T. riparia and the essential oil could be explored to develop a new alternative treatment for leishmaniasis.

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Section: Resultsmentioning

confidence: 99%

Antileishmanial activity of essential oil and 6,7-dehydroroyleanone isolated from Tetradenia riparia

Demarchi

Thomazella

Terron

et al. 2015

Experimental Parasitology

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“…In other studies, infection of macrophages with L. donovani or L. amazonensis per se resulted in HIF-1a accumulation under normoxic conditions, and L. donovani or L. amazonensis was required for pathogen survival within the host cell (19,59). Given that Leishmania species differ greatly in their metabolism (60,61) and that HIF-1a plays an important role in reprogramming the metabolism of macrophages (reviewed in Refs. 62,63), it is tempting to speculate that certain Leishmania species, such as L. donovani or L. amazonensis, require host cell HIF-1a to fuel their metabolic demands.…”

Section: Discussionmentioning

confidence: 99%

Myeloid Cell–Derived HIF-1α Promotes Control of Leishmania major

Schatz

Strüssmann

Mahnke

et al. 2016

The Journal of Immunology

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Hypoxia-inducible factor-1α (HIF-1α), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1α expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major-infected C57BL/6 mice exhibited substantial amounts of HIF-1α in acute cutaneous lesions. In vitro, HIF-1α was required for leishmanicidal activity and high-level NO production by IFN-γ/LPS-activated macrophages. Mice deficient for HIF-1α in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b cells. Together, these data illustrate that HIF-1α is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.

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“…infantum and absent in L . major [ 60 ]. Hence, glyceraldehyde-3-phosphate dehydrogenase was kept to be cytoplasmic in the L .…”

Section: Resultsmentioning

confidence: 99%

Dissecting Leishmania infantum Energy Metabolism - A Systems Perspective

2015

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Leishmania infantum, causative agent of visceral leishmaniasis in humans, illustrates a complex lifecycle pertaining to two extreme environments, namely, the gut of the sandfly vector and human macrophages. Leishmania is capable of dynamically adapting and tactically switching between these critically hostile situations. The possible metabolic routes ventured by the parasite to achieve this exceptional adaptation to its varying environments are still poorly understood. In this study, we present an extensively reconstructed energy metabolism network of Leishmania infantum as an attempt to identify certain strategic metabolic routes preferred by the parasite to optimize its survival in such dynamic environments. The reconstructed network consists of 142 genes encoding for enzymes performing 237 reactions distributed across five distinct model compartments. We annotated the subcellular locations of different enzymes and their reactions on the basis of strong literature evidence and sequence-based detection of cellular localization signal within a protein sequence. To explore the diverse features of parasite metabolism the metabolic network was implemented and analyzed as a constraint-based model. Using a systems-based approach, we also put forth an extensive set of lethal reaction knockouts; some of which were validated using published data on Leishmania species. Performing a robustness analysis, the model was rigorously validated and tested for the secretion of overflow metabolites specific to Leishmania under varying extracellular oxygen uptake rate. Further, the fate of important non-essential amino acids in L. infantum metabolism was investigated. Stage-specific scenarios of L. infantum energy metabolism were incorporated in the model and key metabolic differences were outlined. Analysis of the model revealed the essentiality of glucose uptake, succinate fermentation, glutamate biosynthesis and an active TCA cycle as driving forces for parasite energy metabolism and its optimal growth. Finally, through our in silico knockout analysis, we could identify possible therapeutic targets that provide experimentally testable hypotheses.

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Role of Cytosolic Glyceraldehyde-3-Phosphate Dehydrogenase in Visceral Organ Infection by Leishmania donovani

Cited by 26 publications

References 54 publications

Antileishmanial activity of essential oil and 6,7-dehydroroyleanone isolated from Tetradenia riparia

Antileishmanial activity of essential oil and 6,7-dehydroroyleanone isolated from Tetradenia riparia

Myeloid Cell–Derived HIF-1α Promotes Control of Leishmania major

Dissecting Leishmania infantum Energy Metabolism - A Systems Perspective

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