Genome and transcriptome analyses of Leishmania spp.: opening Pandora’s box

Cruz, Ângela K.; Freitas-Castro, Felipe

doi:10.1016/j.mib.2019.05.004

Cited by 15 publications

(13 citation statements)

References 44 publications

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“…Decoding the genomes of Leishmania species marked an important turning point for the molecular exploration of these pathogens [ 23 – 25 ]. Particularly, recent genomic and transcriptomic studies of Leishmania species significantly advanced our understanding of the genetic plasticity and molecular differences between species/strains, which might be associated with the resistance to antileishmanial drugs and treatment failure [ 22 , 26 – 29 ]. However, it is still challenging to integrate and interpret the genetic features revealed at DNA and RNA levels to elucidate the genetic basis for drug resistance in protozoan parasites.…”

Section: Introductionmentioning

confidence: 99%

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Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Zheng

Chen

et al. 2020

Parasites Vectors

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Background Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease. Methods In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profiling for a recently reported clinical isolate with supposed drug resistance (HCZ), and two reference sensitive strains (DD8 and 9044) of Leishmania donovani, to explore molecular mechanisms underlying drug resistance in this parasite. Results With reference to DD8 and 9044 strains, HCZ isolate showed higher-level virulence and clear resistance to antimonials in promastigote culture, infected macrophages and animal experiment. Pairwise genomic comparisons revealed genetic variations (86 copy number variations, 271 frameshift mutations in protein-coding genes and two site mutations in non-coding genes) in HCZ isolate that were absent from the reference sensitive strains. Proteomic analysis indicated different protein expression between HCZ isolate and reference strains, including 69 exclusively detected proteins and 82 consistently down-/upregulated molecules in the HCZ isolate. Integrative analysis showed linkage of 12 genomic variations (gene duplication, insertion and deletion) and their protein expression changes in HCZ isolate, which might be associated with pathogenic and antimony-resistant phenotype. Functional annotation analyses further indicated that molecules involved in nucleotide-binding, fatty acid metabolism, oxidation-reduction and transport might play a role in host-parasite interaction and drug-resistance. Conclusions This comprehensive integrative work provided novel insights into the genetic basis underlying virulence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases.

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Section: Introductionmentioning

confidence: 99%

“…In the past 30 years, progress has been made in unravelling the infection, genetics and evolution of Leishmania spp. at the molecular level [20][21][22]. Decoding the genomes of Leishmania species marked an important turning point for the molecular exploration of these pathogens [23][24][25].…”

mentioning

confidence: 99%

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Zheng

Chen

et al. 2020

Parasites Vectors

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“…Untargeted transcriptomics to compare treated versus untreated parasites was only performed once in T. cruzi [ 78 ]. However, the evaluation of mRNA transcript abundance in kinetoplastids has mostly been used in fundamental biology studies evaluating changes in expression between the various life cycle stages or to evaluate host-pathogen interactions [ 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. The measurement of RNA levels can provide a broad range of information, but it should be kept in mind that gene expression in kinetoplastids relies on post-transcriptional regulation.…”

Section: Transcriptomicsmentioning

confidence: 99%

Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites

et al. 2020

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Kinetoplastids are the causative agents of leishmaniasis, human African trypanosomiasis, and American trypanosomiasis. They are responsible for high mortality and morbidity in (sub)tropical regions. Adequate treatment options are limited and have several drawbacks, such as toxicity, need for parenteral administration, and occurrence of treatment failure and drug resistance. Therefore, there is an urgency for the development of new drugs. Phenotypic screening already allowed the identification of promising new chemical entities with anti-kinetoplastid activity potential, but knowledge on their mode-of-action (MoA) is lacking due to the generally applied whole-cell based approach. However, identification of the drug target is essential to steer further drug discovery and development. Multiple complementary techniques have indeed been used for MoA elucidation. In this review, the different ‘omics’ approaches employed to define the MoA or mode-of-resistance of current reference drugs and some new anti-kinetoplastid compounds are discussed.

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“…To investigate a possible role of MMA arginine in mRNA metabolism in Leishmania parasites, the N-termini of target RBPs were endogenously HA-tagged, leaving 3'UTRs intact as transcript stability and translational control are overwhelmingly 3'UTR-driven (39). Wild-type and ∆prmt7 parasites were engineered to express HA-tagged Alba3, RBP16, Torus and DDX3 RBPs (Supplementary Figure S2).…”

Section: Loss Of Prmt7 Impacts Rbp Expression and Function In Vivomentioning

confidence: 99%

Post-translational epigenetics: PRMT7 regulates RNA-binding capacity and protein stability to controlLeishmaniaparasite virulence

Ferreira

Dowle

Parry

et al. 2019

Preprint

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RNA binding proteins (RBPs) are the primary gene regulators in kinetoplastids as transcriptional control is nearly absent, making Leishmania an exceptional model for investigating methylation of non-histone substrates. Arginine methylation is an evolutionarily conserved protein modification catalyzed by Protein aRginine MethylTransferases (PRMTs). The chromatin modifier PRMT7 is the only Type III PRMT found in higher eukaryotes and a restricted number of unicellular eukaryotes.In Leishmania major, PRMT7 is a cytoplasmic protein implicit in pathogenesis with unknown substrates. Using comparative methyl-SILAC proteomics for the first time in protozoa, we identified 40 putative targets, including 17 RBPs hypomethylated upon PRMT7 knockout. PRMT7can modify Alba3 and RBP16 trans-regulators (mammalian RPP25 and YBX2 homologs, respectively) as direct substrates in vitro. The absence of PRMT7 levels in vivo selectively reduces Alba3 mRNA-binding capacity to specific target transcripts and can impact the relative stability of RBP16 in the cytoplasm. RNA immunoprecipitation analyses demonstrate PRMT7-dependent methylation promotes Alba3 association with select target transcripts and stability of δ-amastin surface antigen. These results highlight a novel role for PRMT7-mediated arginine methylation upon RBP substrates, suggesting a regulatory pathway controlling gene expression and virulence in Leishmania. This work introduces Leishmania PRMTs as epigenetic regulators of mRNA metabolism with mechanistic insight into the functional manipulation of RBPs by methylation.

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Genome and transcriptome analyses of Leishmania spp.: opening Pandora’s box

Cited by 15 publications

References 44 publications

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites

Post-translational epigenetics: PRMT7 regulates RNA-binding capacity and protein stability to controlLeishmaniaparasite virulence

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