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Experimental evolution links post-transcriptional regulation to Leishmania fitness gain

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F22%3A10443665" target="_blank" >RIV/00216208:11310/22:10443665 - isvavai.cz</a>

  • Result on the web

    <a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=HadhnNwngc" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=HadhnNwngc</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1371/journal.ppat.1010375" target="_blank" >10.1371/journal.ppat.1010375</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Experimental evolution links post-transcriptional regulation to Leishmania fitness gain

  • Original language description

    The protozoan parasite Leishmania donovani causes fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth in promastigote culture (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network associated with parasite fitness gain, with genome instability causing highly reproducible, gene dosage-independent and -dependent changes. Reduction of flagellar transcripts and increase in coding and non-coding RNAs implicated in ribosomal biogenesis and protein translation were not correlated to dosage changes of the corresponding genes, revealing a gene dosage-independent, post-transcriptional mechanism of regulation. In contrast, abundance of gene products implicated in post-transcriptional regulation itself correlated to corresponding gene dosage changes. Thus, RNA abundance during parasite adaptation is controled by direct and indirect gene dosage changes. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence that Leishmania fitness gain in culture may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model for Leishmania fitness gain in culture, where differential regulation of mRNA stability and the generation of modified ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach to Leishmania epidemiology and identifies the Leishmania transcriptome and non-coding small RNome as potential novel sources for the discovery of biomarkers that may be associated with parasite phenotypic adaptation in clinical settings. Author summaryGenome instability plays a central yet poorly understood role in human disease. Gene amplifications and deletions drive cancer development, microbial infection and therapeutic failure. The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in pathogenic systems are unknown. Here we study this important open question in the protozoan parasite Leishmania that causes devastating human diseases termed leishmaniases. Leishmania parasites lack transcriptional control and instead exploit genome instability to adapt to their host environment. Analyzing in vitro adaptation of hamster-derived parasites via gene copy number (genomic level) and gene expression changes (transcriptomic and proteomic levels), we show that these parasites likely exploit small nucleolar RNAs (snoRNAs) to mitigate toxic effects of genome instability by post-transcriptional regulation and the establishment of modified ribosomes. Our findings propose non-coding RNAs as potential novel biomarkers with diagnostic and prognostic value that may be linked to changes in parasite tissue tropism or drug susceptibility. This novel insight into Leishmania adaptation will be likely applicable to other fast evolving eukaryotic systems with unstable genomes, such as fungi or cancer cells.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10600 - Biological sciences

Result continuities

  • Project

  • Continuities

    S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2022

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    PLoS Pathogens

  • ISSN

    1553-7366

  • e-ISSN

    1553-7374

  • Volume of the periodical

    18

  • Issue of the periodical within the volume

    3

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    33

  • Pages from-to

    e1010375

  • UT code for WoS article

    000773099800004

  • EID of the result in the Scopus database

    2-s2.0-85127418046