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Experimental evolution links post-transcriptional regulation to Leishmania fitness gain

Authors :
Laura Piel
K. Shanmugha Rajan
Giovanni Bussotti
Hugo Varet
Rachel Legendre
Caroline Proux
Thibaut Douché
Quentin Giai-Gianetto
Thibault Chaze
Thomas Cokelaer
Barbora Vojtkova
Nadav Gordon-Bar
Tirza Doniger
Smadar Cohen-Chalamish
Praveenkumar Rengaraj
Céline Besse
Anne Boland
Jovana Sadlova
Jean-François Deleuze
Mariette Matondo
Ron Unger
Petr Volf
Shulamit Michaeli
Pascale Pescher
Gerald F. Späth
Parasitologie moléculaire et Signalisation / Molecular Parasitology and Signaling
Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
The Everard and Mina Goodman Faculty of Life Sciences
Bar-Ilan University [Israël]
Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)
Biomics (plateforme technologique)
Plateforme de Protéomique / Proteomics platform
Université Paris Cité (UPCité)-Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio)
Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Charles University [Prague] (CU)
The Mina and Everard Goodman Faculty of Life Sciences
Centre National de Recherche en Génomique Humaine (CNRGH)
Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
This work was supported by the Fondation de la Recherche Médicale contract FDT201805005619 (LP), the Agence Nationale pour la Recherche Labex ‘French Alliance for Parasitology and Health Care’ contract ANR-11-LABX-0024 (GFS, LP, PP, GB) and Labex ‘Integrative Biology of Emerging Infectious Diseases’ contract ANR-10-LABX-62-IBEID, the Campus France Franco-Israeli Programme Hubert Curien Maimonide 2018 (GFS and SM), the France Génomique National infrastructure, funded as part of the « Investissements d’Avenir » program managed by the Agence Nationale pour la Recherche contract ANR-10-INBS-09 (HV, RL, CP), the EU H2020 project LeiSHield-MATI - REP-778298-1 (GS), and the ERD Funds, project CePaViP (CZ.02.1.01/0.0/0.0/ 16_019/0000759) (BV, JS, PV).
We thank the CEA-CNRGH for its contribution to the sequencing costs and all the CEA-CNRGH staff who performed sample preparation and sequencing for their excellent technical assistance
ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011)
ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
European Project: 778298,H2020,H2020-MSCA-RISE-2017,LeiSHield-MATI(2018)
Source :
PLoS Pathogens, PLoS Pathogens, 2022, 18 (3), pp.e1010375. ⟨10.1371/journal.ppat.1010375⟩
Publication Year :
2022
Publisher :
Public Library of Science (PLoS), 2022.

Abstract

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.

Details

ISSN :
15537374 and 15537366
Volume :
18
Database :
OpenAIRE
Journal :
PLOS Pathogens
Accession number :
edsair.doi.dedup.....adc8bea22cdfecdd69b60608036af1bf
Full Text :
https://doi.org/10.1371/journal.ppat.1010375