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Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic
Sarah Hendrickx1, João Luís Reis-Cunha2, Sarah Forrester2
1Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium.
Abstract:
The relatively high post-treatment relapse rates of paromomycin (PMM) in visceral leishmaniasis treatment and the swift emergence of experimental drug resistance challenge its broad application and urge for rational use and monitoring of resistance. However, no causal molecular mechanisms to Leishmania PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected Leishmania donovani clonal lines and the non-cloned preselection population, with variable degrees of PMM resistance, were subjected to whole genome sequencing. To identify genomic variations potentially associated with resistance, SNPs, Indels, chromosomal somy and gene copy number variations were compared between the different parasite lines. A total of 11 short nucleotide variations and the copy number alterations in 39 genes were correlated to PMM resistance. Some of the identified genes are involved in transcription, translation and protein turn-over (transcription elongation factor-like protein, RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3), virulence (major surface protease gp63, protein-tyrosine phosphatase 1-like protein), mitochondrial function (ADP/ATP mitochondrial carrier-like protein), signaling (phosphatidylinositol 3-related kinase, protein kinase putative and protein-tyrosine phosphatase 1-like protein) and vesicular trafficking (ras-related protein RAB1). These results indicate that, in Leishmania, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance.
Insights
High relapse rates and drug resistance necessitate understanding paromomycin (PMM) resistance in leishmaniasis. This study identified genetic variations linked to PMM resistance in Leishmania, revealing impacts on protein translation and multifactorial resistance origins.
Area of Science:
- Molecular Biology
- Parasitology
- Genetics
Background:
- Paromomycin (PMM) is crucial for visceral leishmaniasis treatment.
- High relapse rates and emerging drug resistance limit PMM's effectiveness.
- Molecular mechanisms of PMM resistance in Leishmania remain largely unknown.
Purpose of the Study:
- To investigate the molecular basis of PMM resistance in Leishmania.
- To identify genomic variations associated with experimental PMM resistance.
- To understand the genetic underpinnings of PMM drug resistance.
Main Methods:
- Whole genome sequencing of twelve experimentally selected Leishmania donovani clonal lines with varying PMM resistance.
- Comparative analysis of single nucleotide polymorphisms (SNPs), insertions/deletions (Indels), chromosomal copy number variations, and gene copy number alterations.
- Correlation of identified genomic variations with observed PMM resistance levels.
Main Results:
- Eleven short nucleotide variations and copy number alterations in 39 genes were significantly correlated with PMM resistance.
- Affected genes are involved in crucial cellular processes including transcription, translation, protein turnover, virulence, mitochondrial function, signaling, and vesicular trafficking.
- Specific genes identified include those encoding ribosomal proteins, translation initiation factors, proteasome subunits, and virulence factors like gp63.
Conclusions:
- PMM resistance in Leishmania is complex and likely multifactorial.
- The aminoglycoside PMM impacts protein translational processes in Leishmania.
- Genomic variations, including SNPs and copy number alterations, contribute to PMM resistance.
- Findings provide insights into rational drug use and resistance monitoring strategies for leishmaniasis treatment.
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