Role of oxidative stress and apoptosis in the cellular response of murine macrophages upon<i>Leishmania</i>infection

Deschacht, Maartje; Assche, Tim Van; Hendrickx, Sarah; Bult, Hidde; Maes, Louis; Cos, Paul

doi:10.1017/s003118201200073x

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…They protect against oxidative damage, maintain intracellular redox homeostasis and are also responsible for the maintenance of a reduced trypanothione pool in trypanosomes; essential for their survival, pathogenicity and drug resistance [22], [55], [56]. Leishmania parasites successfully acclimate to oxidative and nitrosative burst conditions encountered during host pathogen interaction; necessary for the establishment of infection [16], [57]. Cysteine is the building block of all thiols and is the precursor molecule for glutathione and trypanothione biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

et al. 2017

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Leishmania donovani is the causative organism of the neglected human disease known as visceral leishmaniasis which is often fatal, if left untreated. The cysteine biosynthesis pathway of Leishmania may serve as a potential drug target because it is different from human host and regulates downstream components of redox metabolism of the parasites; essential for their survival, pathogenicity and drug resistance. However, despite the apparent dependency of redox metabolism of cysteine biosynthesis pathway, the role of L. donovani cysteine synthase (LdCS) in drug resistance and redox homeostasis has been unexplored. Herein, we report that over-expression of LdCS in Amphotericin B (Amp B) sensitive strain (S1-OE) modulates resistance towards oxidative stress and drug pressure. We observed that antioxidant enzyme activities were up-regulated in S1-OE parasites and these parasites alleviate intracellular reactive oxygen species (ROS) efficiently by maintaining the reduced thiol pool. In contrast to S1-OE parasites, Amp B sensitive strain (S1) showed higher levels of ROS which was positively correlated with the protein carbonylation levels and negatively correlated with cell viability. Moreover, further investigations showed that LdCS over-expression also augments the ROS-primed induction of LdCS-GFP as well as endogenous LdCS and thiol pathway proteins (LdTryS, LdTryR and LdcTXN) in L. donovani parasites; which probably aids in stress tolerance and drug resistance. In addition, the expression of LdCS was found to be up-regulated in Amp B resistant isolates and during infective stationary stages of growth and consistent with these observations, our ex vivo infectivity studies confirmed that LdCS over-expression enhances the infectivity of L. donovani parasites. Our results reveal a novel crosstalk between LdCS and thiol metabolic pathway proteins and demonstrate the crucial role of LdCS in drug resistance and redox homeostasis of Leishmania.

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Section: Discussionmentioning

confidence: 99%

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

et al. 2017

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“…iNOS catabolizes L-arginine to nitric oxide (NO) and citrulline [12]. NO, a potent inorganic microbicidal agent, is involved in killing of intracellular invading microorganisms such as Leishmania [11, 15]. In contrast, ARG induced in alternatively activated macrophages hydrolyzes the conversion of the substrate (L-arginine) to L-ornithine and urea.…”

Section: Introductionmentioning

confidence: 99%

Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites

et al. 2017

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Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of the mammalian hosts. In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae. We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes. The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG. Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae. In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages. The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae. We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania. However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling. In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity. In contrast, ARG activity was undetectable in mice inoculated with the non-pathogenic L. tarentolae. Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication. Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice. ARG activity can be used as one of the main marker of the disease severity.

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“…In the present work, we determined the metabolic profile of three genetically similar [as shown by whole genome sequencing (Downing et al ., )] clinical L. donovani strains representing the 3 phenotypes described above (SS, RS and RR). These strains have been extensively phenotyped: from clinical studies on the patients from which they were isolated (Rijal et al ., ) to various in vitro and in vivo phenotyping (Vanaerschot et al ., 2010; 2012; Ouakad et al ., ; Deschacht et al ., ; Hendrickx et al ., ); a table summarizing major features is available as Supporting information (http://onlinelibrary.wiley.com/doi/10.1111/mmi.12374/supinfo). This study was performed on two stages during promastigote growth, with high‐resolution Orbitrap mass spectrometry coupled to ZIC‐HILIC chromatography.…”

Section: Introductionmentioning

confidence: 99%

Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure

Berg

Vanaerschot

Jankevics

et al. 2013

Molecular Microbiology

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SummaryAntimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L. donovani strains with a similar genetic background but different SSGsusceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under Sb III drug pressure.

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Role of oxidative stress and apoptosis in the cellular response of murine macrophages uponLeishmaniainfection

Cited by 19 publications

References 35 publications

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites

Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure

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