Ornithine decarboxylase or gamma-glutamylcysteine synthetase overexpression protects Leishmania (Vianna) guyanensis against antimony

Fonseca, Maísa Santos; Comini, Marcelo A.; Resende, Bethânia V.; Santi, Ana Maria Murta; Zoboli, Antônio P.; Moreira, Douglas S.; Murta, Silvane Maria Fonseca

doi:10.1016/j.exppara.2017.02.001

Cited by 16 publications

(20 citation statements)

References 57 publications

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“…Trypanothione (TSH), a conjugate of GSH and spermidine, is one of the major thiols involved in the maintenance of the intracellular reducing environment in Leishmania parasites for survival . Overexpression of γ ‐GCS has been described in both experimental and clinical isolates of antimony‐resistant Leishmania . Our findings were inconsistent with above‐mentioned studies that demonstrated up‐regulation of γ ‐GCS in all responsive isolates and only in four unresponsive ones.…”

Section: Discussioncontrasting

confidence: 99%

Unresponsiveness to meglumine antimoniate in anthroponotic cutaneous leishmaniasis field isolates: analysis of resistance biomarkers by gene expression profiling

Oliaee

Sharifi

Afgar

et al. 2018

Tropical Med Int Health

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Section: Discussioncontrasting

confidence: 99%

Unresponsiveness to meglumine antimoniate in anthroponotic cutaneous leishmaniasis field isolates: analysis of resistance biomarkers by gene expression profiling

Oliaee

Sharifi

Afgar

et al. 2018

Tropical Med Int Health

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“…Some of the differentially expressed transcripts identi ed in this study corroborate previous proteomic analysis of antimony resistant and susceptible L. infantum lines [22]. In addition, some upregulated transcripts identi ed in this study were also previously investigated by our group, such as gammaglutamylcysteine synthetase [41] elongation factor 2 [42] and mannosyltransferase [43] and these previous results con rmed that they are associated with antimony-resistance phenotype in Leishmania spp.…”

Section: Discussionsupporting

confidence: 89%

“…γ-GCS has been shown to be essential for L. infantum, where it confers protection against oxidative stress and Sb V [81]. An increase of GSH1 mRNA levels also have been reported in some L. tarentolae samples with in vitroinduced resistance to antimony [82] and some Sb V -resistant L. donovani eld isolates [83].Overexpression of γ-GCS is associated with antimony-resistance phenotype in L. guyanensis[41].…”

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confidence: 99%

Comparative transcriptomic analysis of antimony resistant and susceptible Leishmania infantum lines

Andrade

Gonçalves

Liarte

et al. 2020

Preprint

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Background: One of the major challenges for leishmaniasis treatment is the emergence of parasites resistant to antimony. In order to study differentially expressed genes associated with drug resistance we performed a comparative transcriptomic analysis between wild-type and potassium antimonyl tartrate (SbIII)-resistant Leishmania infantum lines using high-throughput RNA sequencing.Methods: All the cDNA libraries were constructed from promastigote forms of each line, sequenced and analyzed using STAR for mapping the reads against the reference genome (L. infantum JPCM5) and DESeq2 for differential expression statistical analyses. All the genes were functionally annotated using sequence similarity search.Results: The analytical pipeline considering an adjusted p-value lower than 0.05 and fold change greater than 2.0 identified 933 transcripts differentially expressed (DE) between wild-type and SbIII-resistant L. infantum lines. Out of 933 DE transcripts, 504 presented functional annotation and 429 were assigned as hypothetical proteins. A total of 837 transcripts were upregulated and 96 were downregulated in the SbIII-resistant L. infantum line. Using this DE dataset, the proteins were further grouped in functional classes according to the Gene Ontology database. The functional enrichment analysis for biological processes showed that the upregulated transcripts in the SbIII-resistant line are associated with protein phosphorylation, microtubule-based movement, ubiquitination, host-parasite interaction, cellular process and other categories. The downregulated transcripts in the SbIII-resistant line are assigned in the GO categories: ribonucleoprotein complex, ribosome biogenesis, rRNA processing, nucleosome assembly and translation.Conclusions: The transcriptomic profile of L. infantum showed a robust set of genes from different metabolic pathways associated with antimony resistance phenotype in this parasite. Our results address the complex and multifactorial antimony resistance mechanisms in Leishmania, identifying several candidate genes that may be further evaluated as molecular targets for chemotherapy of leishmaniasis.

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“…Conversely, Leishmania heterozygous mutants, having only one GSH1 -allele, synthesized less glutathione and trypanothione, and consequently showed a significant decreased survival in the presence of Sb V compared with control cells ( Mukherjee et al, 2009 ). In a recent article, it was shown that L. guyanensis parasites overexpressing GSH1 presented an increase of 4-fold in Sb III -resistance index when compared with the wild-type line ( Fonseca et al, 2017 ). Interestingly, our data showed that transcript LinJ.18.T1660 (encoding for γGCS) was about 2.5-fold more abundant in the resistant S line than in the WT parasites.…”

Section: Resultsmentioning

confidence: 99%

Genomic and transcriptomic alterations in Leishmania donovani lines experimentally resistant to antileishmanial drugs

Rastrojo

García-Hernández

Vargas

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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Leishmaniasis is a serious medical issue in many countries around the World, but it remains largely neglected in terms of research investment for developing new control and treatment measures. No vaccines exist for human use, and the chemotherapeutic agents currently used are scanty. Furthermore, for some drugs, resistance and treatment failure are increasing to alarming levels. The aim of this work was to identify genomic and trancriptomic alterations associated with experimental resistance against the common drugs used against VL: trivalent antimony (SbIII, S line), amphotericin B (AmB, A line), miltefosine (MIL, M line) and paromomycin (PMM, P line). A total of 1006 differentially expressed transcripts were identified in the S line, 379 in the A line, 146 in the M line, and 129 in the P line. Also, changes in ploidy of chromosomes and amplification/deletion of particular regions were observed in the resistant lines regarding the parental one. A series of genes were identified as possible drivers of the resistance phenotype and were validated in both promastigotes and amastigotes from Leishmania donovani, Leishmania infantum and Leishmania major species. Remarkably, a deletion of the gene LinJ.36.2510 (coding for 24-sterol methyltransferase, SMT) was found to be associated with AmB-resistance in the A line. In the P line, a dramatic overexpression of the transcripts LinJ.27.T1940 and LinJ.27.T1950 that results from a massive amplification of the collinear genes was suggested as one of the mechanisms of PMM resistance. This conclusion was reinforced after transfection experiments in which significant PMM-resistance was generated in WT parasites over-expressing either gene LinJ.27.1940 (coding for a D-lactate dehydrogenase-like protein, D-LDH) or gene LinJ.27.1950 (coding for an aminotransferase of branched-chain amino acids, BCAT). This work allowed to identify new drivers, like SMT, the deletion of which being associated with resistance to AmB, and the tandem D-LDH-BCAT, the amplification of which being related to PMM resistance.

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Ornithine decarboxylase or gamma-glutamylcysteine synthetase overexpression protects Leishmania (Vianna) guyanensis against antimony

Cited by 16 publications

References 57 publications

Unresponsiveness to meglumine antimoniate in anthroponotic cutaneous leishmaniasis field isolates: analysis of resistance biomarkers by gene expression profiling

Unresponsiveness to meglumine antimoniate in anthroponotic cutaneous leishmaniasis field isolates: analysis of resistance biomarkers by gene expression profiling

Comparative transcriptomic analysis of antimony resistant and susceptible Leishmania infantum lines

Genomic and transcriptomic alterations in Leishmania donovani lines experimentally resistant to antileishmanial drugs

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