Leishmaniaspp.: Nitric Oxide-Mediated Metabolic Inhibition of Promastigote and Axenically Grown Amastigote Forms

Lemesre, Jean-Loup; Sereno, Denis; Daulouède, Sylvie; Veyret, B.; Brajon, Nathalie; Vincendeau, Philippe

doi:10.1006/expr.1997.4151

Cited by 67 publications

(47 citation statements)

References 19 publications

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“…The exact molecular mechanism through which this radical promotes intracellular killing of Leishmania is not yet fully defined. However, it may be mentioned that NO also inhibits Leishmania cysteine proteinase activity, a known virulence factor, leading to lethal metabolic inhibition through irreversible chemical modification of reactive cysteine residues (35) as well as blocking the differentiation process from amastigotes to promastigotes (36). These observations are indicative of the essential role of reactive nitrogen intermediates in the control of intracellular parasites by murine macrophages, exerting lytic effects on both parasite developmental stages.…”

Section: Discussionmentioning

confidence: 99%

18β-Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF-κB

Ukil

Biswas

Das

et al. 2005

The Journal of Immunology

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The efficacy of 18β-glycyrrhetinic acid (GRA), a pentacyclic triterpene belonging to the β-amyrin series of plant origin, was evaluated in experimental visceral leishmaniasis. GRA is reported to have antitumor and immunoregulatory activities, which may be attributable in part to the induction of NO. Indeed, an 11-fold increase in NO production was observed with 20 μM GRA in mouse peritoneal macrophages infected with Leishmania donovani promastigotes. In addition to having appreciable inhibitory effects on amastigote multiplication within macrophages (IC50, 4.6 μg/ml), complete elimination of liver and spleen parasite burden was achieved by GRA at a dose of 50 mg/kg/day, given three times, 5 days apart, in a 45-day mouse model of visceral leishmaniasis. GRA treatment resulted in reduced levels of IL-10 and IL-4, but increased levels of IL-12, IFN-γ, TNF-α, and inducible NO synthase, reflecting a switch of CD4+ differentiation from Th2 to Th1. This treatment is likely to activate immunity, thereby imparting resistance to reinfection. GRA induced NF-κB migration into the nucleus of parasite-infected cells and caused a diminishing presence of IκB in the cytoplasm. The lower level of cytoplasmic IκBα in GRA-treated cells resulted from increased phosphorylation of IκBα and higher activity of IκB kinase (IKK). Additional experiments demonstrated that GRA does not directly affect IKK activity. These results suggest that GRA exerts its effects at some level upstream of IKK in the signaling pathway and induces the production of proinflammatory mediators through a mechanism that, at least in part, involves induction of NF-κB activation.

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Section: Discussionmentioning

confidence: 99%

18β-Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF-κB

Ukil

Biswas

Das

et al. 2005

The Journal of Immunology

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“…Studies on human cutaneous leishmaniasis reveal that Leishmania killing is associated with NO production (40). Moreover, the capacity of canine macrophages to eliminate intracellular amastigotes through a NO-dependent mechanism has been documented (46,55,59).NO-dependent cytostatic and/or cytotoxic activities by activated macrophages on various parasites have been clearly demonstrated (20,26,29,33,57). In Leishmania infections, NO-generating creams applied topically to lesions revealed a modest efficacy in mouse models, whereas they were able to cure human patients (15, 65).…”

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confidence: 99%

Nitric Oxide-Mediated Proteasome-Dependent Oligonucleosomal DNA Fragmentation inLeishmania amazonensisAmastigotes

et al. 2002

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Resistance to leishmanial infections depends on intracellular parasite killing by activated host macrophages through the L-arginine-nitric oxide (NO) metabolic pathway. Here we investigate the cell death process induced by NO for the intracellular protozoan Leishmania amazonensis. Exposure of amastigotes to moderate concentrations of NO-donating compounds (acidified sodium nitrite NaNO 2 or nitrosylated albumin) or to endogenous NO produced by lipopolysaccharide or gamma interferon treatment of infected macrophages resulted in a dramatic time-dependent cell death. The combined use of several standard DNA status analysis techniques (including electrophoresis ladder banding patterns, YOPRO-1 staining in flow cytofluorometry, and in situ recognition of DNA strand breaks by TUNEL [terminal deoxynucleotidyltransferase-mediated dUTPbiotin nick end labeling] assay) revealed a rapid and extensive fragmentation of nuclear DNA in both axenic and intracellular NO-treated amastigotes of L. amazonensis. Despite some similarities to apoptosis, the nuclease activation responsible for characteristic DNA degradation was not under the control of caspase activity as indicated by the lack of involvement of cell-permeable inhibitors of caspases and cysteine proteases. In contrast, exposure of NO-treated amastigotes with specific proteasome inhibitors, such as lactacystin or calpain inhibitor I, markedly reduced the induction of the NO-mediated apoptosis-like process. These data strongly suggest that NO-induced oligonucleosomal DNA fragmentation in Leishmania amastigotes is, at least in part, regulated by noncaspase proteases of the proteasome. The determination of biochemical pathways leading up to cell death might ultimately allow the identification of new therapeutic targets.Leishmania spp. are obligate intracellular protozoan parasites of macrophages that are responsible for a wide range of human diseases, including self-healing skin lesions, diffuse cutaneous and mucosal lesions, or fatal visceral infections. In the Leishmania life cycle, two principal parasite forms exist: (i) the amastigote form that develops inside mononuclear phagocytes of a vertebrate host and (ii) the motile promastigote form that develops in the vector gut. The various possible outcomes of leishmanial infection have been associated with expansion of specific T helper lymphocyte populations (52). Immune control of leishmaniasis involves a dominant Th1 response, leading to macrophage activation and elimination of intracellular parasites through the induction of nitric oxide synthase (NOS II) and NO synthesis from L-arginine. This prototypical model has been largely evidenced in murine leishmaniasis (17,22,33). Human activated macrophages can also induce antileishmanial activity via the L-arginine NO pathway (44,58,60). Studies on human cutaneous leishmaniasis reveal that Leishmania killing is associated with NO production (40). Moreover, the capacity of canine macrophages to eliminate intracellular amastigotes through a NO-dependent mechanism has been docum...

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“…Indeed, cis-conitase and GAPDH, key enzymes of the Krebs cycle and the glycolytic pathway, have had their ac-tivities inhibited in Leishmania exposed to different NO donors (Lemesre et al, 1997;Mauel and Ransijn, 1997). Interestingly, an increase in the activity of GAPDH and cis-aconitase was demonstrated in L. infantum promastigotes showing resistance to NO (Holzmuller et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Such interaction may lead to an inhibition of the catalytic action of enzymes that are essential for microorganism survival, including cis-aconitase (Lemesre et al, 1997) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Mauel et al, 1991). It was previously demonstrated that these two enzymes had higher activity levels in strains of Leishmania infantum with induced resistance to NO (Holzmuller et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Expression of glyceraldehyde 3-phosphate dehydrogenase is enhanced in Leishmania spp naturally resistant to nitric oxide

et al. 2015

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ABSTRACT. Leishmania spp are the causative agents of a spectrum of diseases termed leishmaniasis that affect mammals, including humans and dogs. Although reactive nitrogen species are employed in the control of parasitism by the immune system, it is known that Leishmania can withstand this oxidative stress. As the mechanism by which these species are resistant to nitric oxide (NO) is poorly understood, the main objective of this study was to evaluate the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in Leishmania amazonensis and Leishmania chagasi promastigotes showing natural resistance to NO. GAPDH transcript levels were quantified by real-time polymerase chain reaction amplification, and GAPDH activity (assessed by levels of NADH oxidation) was measured by spectrophotometry. The level of nitration in total protein was assessed by immunoblotting. The results demonstrated an increase in GAPDH expression in resistant isolates of both species compared to susceptible isolates. The increase in GAPDH expression led to an increase in the activity of GAPDH in L. amazonensis human isolates resistant to NO. The pattern of protein nitration did not differ between sensitive and resistant isolates. Our results suggest that changes in expression of GAPDH may be responsible, at least in part, to natural resistance to NO found in human and canine Leishmania spp.

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Leishmaniaspp.: Nitric Oxide-Mediated Metabolic Inhibition of Promastigote and Axenically Grown Amastigote Forms

Cited by 67 publications

References 19 publications

18β-Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF-κB

18β-Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF-κB

Nitric Oxide-Mediated Proteasome-Dependent Oligonucleosomal DNA Fragmentation inLeishmania amazonensisAmastigotes

Expression of glyceraldehyde 3-phosphate dehydrogenase is enhanced in Leishmania spp naturally resistant to nitric oxide

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