Leishmania tolerance and resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB27329 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2653345_1.fastq.gz | Fastqsanger.gz | |||
| ERR2653345_2.fastq.gz | Fastqsanger.gz | |||
| ERR2653346_1.fastq.gz | Fastqsanger.gz | |||
| ERR2653346_2.fastq.gz | Fastqsanger.gz | |||
| ERR2653347_1.fastq.gz | Fastqsanger.gz |
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Project description:Leishmaniasis is caused by parasitic protozoa of the genus Leishmania and is found widely across the tropics and sub-tropics, afflicting hundreds of thousands of people. The disease is notoriously difficult to treat. Here, we present evidence of the existence of persister-like cells in cultured Leishmania populations, induced upon exposure to normally lethal doses of antimony, a widely used anti-leishmanial. Persisters are a small fraction of non-proliferative cells with reduced metabolism that are adapted to withstand a variety of environmental assaults, including lethal doses of antimicrobials. We show that Leishmania persister-like cells survive lethal doses of antimonials by adopting a quiescence phenotype characterised by reduced proliferation, constrained metabolism, and diminished mitochondrial membrane potential. What is more, these cells demonstrate cross-tolerance to other anti-leishmanial drugs. Wild-type persister-like cells reverted to similar levels of drug susceptibility once the antimony-induced pressure was removed. Surprisingly, cells which had previously been selected for genetic changes causing resistance to antimony acquired a level of hyper-resistance after transient passage through the quiescent state, without further genetic change. Our results demonstrate the extreme versatility of this eukaryotic pathogen in adaptation to drug pressure and highlight the need for the development of new anti-leishmanials targeting non-proliferative forms.
2025-11-22 | GSE310227 | GEO
Project description:Purpose: In this study, we have used a translatomic approach by coupling polysome profiling and deep RNA-sequencing to estimate changes in the translatome of antimony-resistant Leishmania parasites Methods: Leishmania tropica promastigotes were stepwise selected for resistance to trivalent antimony. Two different strains were studied, the L. tropica SbIII-sensitive or wildtype strain (WT) and the derived highly resistant strain (HR). After polysome profiling four types of samples were evaluated by deep RNAseq: total mRNA used as input, monosomes (MS), light polysomes (LP), and heavy polysomes (HP). The DESeq2 algorithm was used for differential expression analysis to identify translational changes at the basal level (HR Vs. WT), translational changes to combat the drug (HR+SbIII Vs. HR), and to compare translatomic Vs. transcriptomic changes (HP Vs. Total input) [see overall design section below]. Results: Differential translational analysis (cutoff of fold change ≥ 1.5 and p-value corrected by Benjamini-Hochberg FDR ≤ 0.05) showed that transcripts composition per polysome fraction was different in the resistant strain. It included several upregulated (Up) and downregulated (Down) transcripts. At the basal level, 2431 different transcripts were differentially translated: monosome (Down: 4, Up: 0), light polysomes (Down: 906, Up: 951), and heavy polysomes (Down: 1096, Up: 1064). Under the antimony challenge, 189 different transcripts were differentially translated: monosome (Down: 0, Up: 2), light polysomes (Down: 9, Up: 57), and heavy polysomes (Down: 30, Up: 134). Overall, most of the changes were identified in polysome fraction when compared with monosomes or total transcriptome. Conclusions: Our study shows evidence that translational control has a main role in coordinating the resistance to antimony in Leishmania parasites. We propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes in Leishmania parasites.
2023-04-04 | GSE173848 | GEO
Project description:Background: Drug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we investigate molecular alterations in antimony resistance in the New World species L. amazonensis. Methods/Principal Findings: We selected populations of L. amazonensis for resistance to antimony by step-wise drug pressure. Gene expression of highly resistant mutants was studied using DNA microarrays. RNA expression profiling of antimony-resistant L. amazonensis revealed the overexpression of genes involved in drug resistance including the ABC transporter MRPA and several genes related to thiol metabolism. The MRPA overexpression was validated by quantitative real-time PCR and further analysis revealed that this increased expression was correlated to gene amplification as part of extrachromosomal linear amplicons in some mutants and as part of supernumerary chromosomes in other mutants. The expression of several other genes encoding hypothetical proteins but also nucleobase and glucose transporter encoding genes were found to be modulated. Conclusions/Significance: Mechanisms classically found in Old World antimony resistant Leishmania were also highlighted in New World antimony-resistant L. amazonensis. These studies were useful to the identification of resistance molecular markers.
2011-06-11 | GSE26159 | GEO
Project description:Leishmania are ancient eukaryotes that have retained the ability to produce extracellular vesicles (EVs) through evolution. Until date, it was unclear if different DNA entities could be associated to Leishmania EVs, and whether these could constitute a novel mechanism of horizontal gene transfer (HGT). Herein, we investigated the DNA content of EVs derived from drug-resistant parasites, as well as the potential of EVs as shuttles for DNA transfer. Next-generation sequencing, and PCR assays confirmed the enrichment of amplicons carrying drug-resistance genes associated to EVs. Transfer assays of drug-resistant EVs highlighted a significant impact in the phenotype of recipient parasites induced by the expression of the transferred DNA. Recipient parasites displayed an enhanced growth and better control of oxidative stress. We provide the first evidence that eukaryotic EVs function as efficient mediators in HGT, thereby facilitating the transmission of drug-resistance genes and increasing the fitness of cells when encountering stressful environments.
2022-07-19 | GSE200222 | GEO
Project description:Infection with antimony resistant (SbR) but not with sentitive (SbS) Leishmania donovani (LD) gives rise to aggressive pathology in mammalian hosts, the cause of which is far from clear. Some intracellular pathogens exploit autophagy for their own benefit. Here we show that induction of autophagy in normal macrophages (MF) by pharmacological mediators prior to infection with SbRLD (SbRLD-MF) enhanced their growth as compared to untreated MF, unlike SbSLD-MF. Autophagy was evident in SbRLD-MF from electron microscopical studies showing double membrane-bound compartment around amastigote. In SbRLD-MF there is induction of beclin 1, which forms the platform to recruit other interacting molecules to initiate autophagy. Knocking down the beclin 1 transcription factor Nrf2 and subsequent infection with SbRLD showed significantly lower organ parasites as compared to wild type BALB/c mice. Cessation of autophagy in SbRLD-MF at the later stage of infection is coupled with induction of miR-30a, whose binding to 3'UTR of beclin 1 leads to its post-transcriptional attenuation followed by rise in intracellular Ca++ and apoptosis. SbRLD mediated translocation of AP-1 transcription factor to the nucleus induce pri-miR-30a over-expression. Rise in Ca++ causes caspase 8 activtion leading to the cleavage of beclin 1 and initiation of apoptosis in SbRLD-MF. Apoptosis may favor parasite egress for cell to cell transmission. We also found that beclin 1 expression is present in splenocytes of kala-azar patients harbouring SbRLD but not SbSLD. Our results suggest that SbRLD has evolved a unique mechanism for its own benefit which explains, in part, the cause of aggressive pathology. Peritoneal exudate macrophages were isolated from mouse, grown in 60mm plates and infected with Leishmania donovani and total RNA was isolated from cells at 12, 18 and 24 hrs post infection. Leishmania infected macrophage miRNA expression signature was generated. Cells grown on 60mm plates and infected with Leishmania. The main objective of the microarray analysis of mmu-miRNA in antimony resistant and antimony sensitive Leishmania donovani infected macrophages are as follows: 1. To study how the expression of miRNA varies in either antimony resistant or antimony sensitive Leishmania infected macrophages as compared to the normal macrophages as a function of time. LPS was used as control. 2. To study the expression of those miRNAs which are differentially expressed in antimony resistant and antimony sensitive Leishmania infected macrophages at each time point post infection. 3. To identify those miRNAs which are responsible for degradation of autophagy initiating protein beclin 1 mRNA
2014-04-25 | E-GEOD-57042 | biostudies-arrayexpress
Project description:Drug resistance threatens the effective control of infections, including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial control, but their role in drug-resistant infections is poorly understood. Here, we evaluated human neutrophil response to clinical parasite strains having distinct natural drug susceptibility. We found that Leishmania antimony drug resistance significantly altered the expression of neutrophil genes, some of them transcribed by specific neutrophil subsets. Infection with drug-resistant parasites increased the expression of detoxification pathways and reduced the production of cytokines. Among these, the chemokine CCL3 was predominantly impacted, which resulted in an impaired ability of neutrophils to attract myeloid cells. Moreover, decreased myeloid recruitment when CCL3 levels are reduced was confirmed by blocking CCL3 in a mouse model. Collectively, these findings reveal that the interplay between naturally drug-resistant parasites and neutrophils modulates the infected skin immune microenvironment, revealing a key role of neutrophils in drug resistance.
2024-04-23 | GSE244972 | GEO
Project description:The mRNA expression of antimony resistant strains of Leishmania donovani was compared to the expression of the sensitive Leishmania donovani.
2016-01-01 | GSE62468 | GEO
Project description:The mRNA expression of antimony resistant strains of Leishmania donovani was compared to the expression of the sensitive Leishmania donovani. The antimony resistant and sensitive Leishmania donovani were grown in complete M199 medium with 10% FCS and Penicillin streptomycin mixture. At stationary phase (5 day culture) cells were harvested in sterile Phosphate buffered saline and used for RNA isolation.
2016-07-03 | E-GEOD-62468 | biostudies-arrayexpress
Project description:Antimony resistance in Leishmania guyanensis
| PRJEB6114 | ENA
Project description:Here, we used shotgun proteomics (LC-MS/MS) to identify changes in the proteome of antimony resistant parasites growing under drug challenge. We used a Leishmania tropica strain that was selected in vitro to resist high levels of trivalent antimony. Two experimental conditions were evaluated: a resistant strain grown without drug challenge (control), and a resistant strain grown under drug challenge (treatment). Three independent biological replicates were used per experimental condition.
2022-06-07 | MSV000089617 | GNPS