Post-transcriptional regulation of Leishmania fitness gain
Posted on: 5 April 2021 , updated on: 21 April 2021
Preprint posted on 22 March 2021
Leishmania parasites adapt by adjusting gene copy number, mRNA stability and the efficiency of protein synthesis.
Selected by Joao Mello-VieiraCategories: microbiology, molecular biology
Background
Parasites of the genus Leishmania cause a spectrum of diseases known collectively as leishmaniases. These parasites cause over 12 million infections worldwide, making it one of the five most important parasitic diseases on the planet. One curious aspect of the molecular biology of Leishmania parasites is their plastic or unstable genome. These parasites can vary the copy number of individual genes and even chromosomes to adapt to different conditions. Some of these changes are linked to the ability to develop drug resistance or different tissue tropism in individual parasites. However, how do Leishmania parasites deal with such an unstable genome and the deleterious effects of gene dosage, because of the variations in the number of genes and chromosomes?
In this preprint, Piel and colleagues study the mechanisms of evolution of the L. donovani parasites to better understand how these parasites adapt. To induce experimental evolution, L. donovani parasites were grown in in vitro cell culture conditions for 190 generations (approximately 20 weeks in culture), where the medium is rich in nutrients and there is no immune system to evade. After adaptation, the authors compared these new culture-adapted parasites with parasites that were kept in culture for only 20 generations. This allowed them to observe how the parasites modified the expression of their genes after so many generations and if there were any costs to this experimental evolution. They looked at the number of chromosomes, the levels of mRNA and the amount of proteins to discern the different layers of regulation during adaptation and evolution.
Key findings
- L. donovani parasites that were adapted long term to in vitro culture show less ability to infect macrophages and to differentiate into the next stage of their life cycle. Conversely, parasites that are not adapted to in vitro culture are better at infecting macrophages and differentiating. This means that accelerated growth in vitro was gained with attenuation of virulence in vivo.
- Comparing the karyotypes of these two parasite strains, the authors observed aneuploidy, which is the presence of an abnormal number of chromosomes. In fact, L. donovani adaptation to cell culture was accompanied by triploidy of several chromosomes.
- When looking at the transcriptomes, the authors observed that culture-adapted parasites express more genes related to ribosome biogenesis and assembly, translation and non-coding RNA processing. However, this variation was not fully explained by the variation in the number of chromosomes, suggesting that there is another mechanism of gene regulation besides copy number variation.
- Also, the authors performed proteomics and observed that presence of some proteins did not correlate with either the gene copy number or the abundance of mRNA transcripts. This suggests that there is a new layer of regulation after mRNA post-transcriptional regulation.
- Parasite adaptation to cell culture also increased the levels of some small nucleolar RNAs. These non-coding RNAs have the ability to modify rRNAs and thus regulate translation. In fact, higher levels of rRNA pseudouridylation were observed in culture-adapted strains, suggesting a translational control mechanism during adaptation.
Importance
Leishmania parasites have two life cycle phases , one extracellular phase in the midgut of sand flies and another intracellular phase inside macrophages of mammals. As such, the adaptation to different environments is crucial for transmission and success of the infection. To better survive, parasites need to express the proper genes and proteins for the host and the tissue they are colonizing.
Importantly, Leishmania parasites cannot control protein levels by transcriptional control of their genes, as most eukaryotes. These organisms cannot simply turn on one gene at a time because their gene expression is more similar to bacterial operons, expressing multiple protein coding genes at the same time in long polycistronic units. These polycistronic transcripts are trans-spliced and polyadenylated to generate one mature mRNA transcript per coding gene. As such, in Leishmania, mRNA abundance is regulated by gene copy number (more gene copies, more expression) or post-transcriptionally (each mature mRNA is individually regulated).
This study on experimental evolution by Piel and colleagues, adds another layer of regulation, as small nucleolar RNAs change ribosomes by pseudouridylation, thus creating ribosomes that have a higher preference for certain mRNAs. In fact, rRNA pseudouridylation affects ribosomal-mRNA binding and translational fidelity in human and yeast cells. This way Leishmania parasites might be able to select which mRNAs are behind translated into proteins, avoiding the expression of deleterious proteins after chromosome duplication. It will be interesting to see how mRNAs are being selected for translation, and if messenger RNA modifications work in tandem with ribosomal RNA modifications to create this subset of translatable transcripts.
Genomic instability can be thought as a necessary part for adaptation and evolution for some organisms. In fact, cancer cells take advantage of their genomic instability as a driver for advantageous mutations and chromosomal rearrangements. Genomic instability therefore creates a genetically heterogenous population that has better chances of survival given a new stimulus (such as antibiotics, drugs, the immune system). This new manuscript explores an innovative way through which eukaryotic cells deal with genomic instability by modifying ribosomes, the components of the cell that are responsible for protein synthesis. This discovery might be useful to understand how other organisms deal with their own genomic instability and provide therapeutic options to deregulate it.
doi: https://doi.org/10.1242/prelights.27991
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the microbiology category:
Green synthesized silver nanoparticles from Moringa: Potential for preventative treatment of SARS-CoV-2 contaminated water
Safieh Shah, Benjamin Dominik Maier
Intracellular diffusion in the cytoplasm increases with cell size in fission yeast
Leeba Ann Chacko, Sameer Thukral
Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA
Leeba Ann Chacko
Also in the molecular biology category:
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Green synthesized silver nanoparticles from Moringa: Potential for preventative treatment of SARS-CoV-2 contaminated water
Safieh Shah, Benjamin Dominik Maier
Non-disruptive inducible labeling of ER-membrane contact sites using the Lamin B Receptor
Jonathan Townson
preListsmicrobiology category:
in theBioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
List by | Dey Lab, Samantha Seah |
1
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
List by | Dey Lab |
Antimicrobials: Discovery, clinical use, and development of resistance
Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.
List by | Zhang-He Goh |
Also in the molecular biology category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
List by | Sandra Franco Iborra |