Dataset Information

Translational Reprogramming as a Driver of Antimony-drug Resistance

ABSTRACT: Drug resistance is a major mitigating factor for leishmaniasis treatment, resulting in reduced therapeutic efficacy of pentavalent antimonials, the main antileishmanial drug. Nevertheless, the molecular mechanisms modulating the antimony-resistant phenotypes remain poorly understood. Since Leishmania parasites have limited use of transcriptional control, post-transcriptional mechanisms take a prominent role in the coordination of gene expression. Here, we used a translatomic approach, coupling polysome profiling and deep RNA-sequencing to determine if the resistance to antimony is modulated at the translational level. The translatome of the antimony-resistant strain (HR) was dramatically different from the sensitive strain (WT) even in the absence of the drug and included 2431 differentially translated transcripts. Our data support that during the development of drug resistance remodelling of translation serves as a preemptive adaptation to efficiently compensate for the loss of biological fitness once they are exposed to the antimony. In contrast, drug-resistant parasites exposed to antimony drug (HR + SbIII) modulate a selective translation of o189 transcripts involved in interconnected biological processes, such as improved energy metabolism and oxidant response, drug inactivation, surface protein remodelling, and drug efflux. The translatome data were validated by RT-qPCR and proteomic analyses, identifying not only previously reported antimony-resistance markers, but also several potentially new ones. Thus, antimony-resistant parasites display a complex, preemptive adaptation to the drug through global translatome remodelling in comparison with sensitive parasites, we hypothesize that these changes allow for a highly targeted and coordinated response to drug challenges. A comparison between the total transcriptome versus the translatome (heavy polysomes) showed that most of the changes detected in antimony-resistant parasites are detected at the translational level. Classification of gene variants and differentially translated transcripts consistently highlighted the importance of mRNA translation components, surface protein rearrangement, optimized energy metabolism, and improved antioxidant response. Here, we propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes.

ORGANISM(S): Leishmania tropica

SUBMITTER:

PROVIDER: S-BSST850 | biostudies-other |

SECONDARY ACCESSION(S): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173848

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

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.

Dataset Information

Translational Reprogramming as a Driver of Antimony-drug Resistance

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets