Leishmania: Responding to environmental signals and challenges without regulated transcription

Abstract

Here we describe the non-canonical control of gene expression in Leishmania, a single-cell parasite that is responsible for one of the major neglected tropical diseases. We discuss the lack of regulated RNA synthesis, the post-transcriptional gene regulation including RNA stability and regulated translation. We also show that genetic adaptations such as mosaic aneuploidy, gene copy number variations and DNA sequence polymorphisms are important means for overcoming drug challenge and environmental diversity. These mechanisms are discussed in the context of the unique flow of genetic information found in Leishmania and related protists.

Keywords: Aneuploidy; Gene copy number; Leishmania; Translational regulation.

Fig. 1

Polycistronic transcription and RNA processing in Leishmania. The figure shows the distribution of coding sequences (CDSs) on the L. donovani chromosome 2. Arrows in red signify upper strand CDSs, green arrows indicate lower strand CDSs. Polycistronic transcripts are generated and processed into mature, monocistronic mRNA by trans-splicing of a 39-nucleotide spliced leader RNA (SL) and coupled poly-adenylation (poly A). The SL also contributes the CAP structure (yellow diamond) to the mRNA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Constitutive and selected aneuploidy in Leishmania donovani selected under IC₅₀ of a pteridin reductase 1 inhibitor (PTR1-i) or an equivalent dose of solvent (DMSO) for 40 days. (A) NGS read alignment densities were established for each chromosome using the Bowtie2 algorithm, normalised against the overall average read density set at 2, and displayed as heat map. Note that i) chromosome 31 is constitutively tetrasomic, ii)chromosomes 8, 12, and 24 are constitutively trisomic, and chromosome 23 shows trisomy after PTR1-i selection. In addition, chromosome 5 shows an intermediate ploidy indicating mosaic aneuploidy or partial chromosome amplification. (B) Sequence read alignment over chromosome 5 for DMSO- (upper panel) or PTR1-i-selected (lower panel) shows equal relative read distribution, indicating mosaic aneuploidy for chromosome 5 in the PTR1-i-selected population.