Abstract

Objectives: This literature review aims to summarize the current knowledge regarding the genome plasticity observed within the genome of the Leishmania parasite, and to discuss how genome plasticity contributes to the adaptation of the parasite and to development of a drug resistant state.
Materials and Methods: The search terms “Leishmania” and “genome plasticity”, were used to search the PubMed database for relevant papers, published between the years 2000 and 2020.
Results: Aneuploidy within the Leishmania genome allows for drug resistance and adaptation to the environment. In addition copy number variation promotes the up regulation of genes conferring drug resistant capabilities to the parasite.
Conclusion: Drug-resistant Leishmania mutants display differential patterns of chromosomal somy when compared to wild-type strains. Highlighting a role for mosaic aneuploidy in the development of drug resistance. Leishmania parasites in the amastigote life cycle stage display differential gene copy numbers compared to parasites in the promastigote life cycle stage. Suggesting that copy number variation contributes to parasite adaptation to the environment.
*This paper was published by Scientific Scholar and has been archived here.*

Keywords: Leishmania Genome plasticity Leishmania adaptation

References

  1. Stuart K, et al. Kinetoplastids: Related protozoan pathogens, different diseases. J Clin Invest. 2008;118:1301-10.
  2. Okwor I, Uzonna J. Social and economic burden of human leishmaniasis. Am J Trop Med Hygiene. 2016;94:489-93.
  3. CDC. Parasites - Leishmaniasis [online] 2020. Available at: https://www.cdc.gov/parasites/leishmaniasis/index.html#:~:text=Leishmaniasis%20is%20a%20parasitic%20disease,bite%20of%20phlebotomine%20sand%20flies [Accessed 29 December 2020]
  4. Gurel MS, et al. Cutaneous leishmaniasis: A great imitator. Clin Dermatol. 2020;38:140-51.
  5. Bi K, et al. Current visceral leishmaniasis research: A research review to inspire future study. BioMed Res Int. 2018;9872095
  6. WHO. Leishmaniasis [online] Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis [Accessed 29 December 2020]
  7. Sereno D, et al. Meta-analysis and discussion on challenges to translate leishmania drug resistance phenotyping into the clinic. Acta Tropica. 2019;191:204-11.
  8. Reis-Cunha JL, et al. Gene and chromosomal copy number variations as an adaptive mechanism towards a parasitic lifestyle in trypanosomatids. Curr Genom. 2018;19:87-97.
  9. Damasceno JD, et al. Read, write, adapt: Challenges and opportunities during kinetoplastid genome replication. Trend Genet. 2021;37:21-34.
  10. Sterkers Y, et al. FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major. Cell Microbiol. 2011;13:274-283.
  11. Selmecki A, et al. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313:367-70.
  12. Reis-Cunha JL, et al. Whole genome sequencing of Trypanosoma cruzi field isolates reveals extensive genomic variability and complex aneuploidy patterns within TcII DTU. BMC Genom. 2018;19:816.
  13. Rogers MB, et al. Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania. Genome Res. 2011;21:2129-42.
  14. Sterkes Y, et al. Parasexuality and mosaic aneuploidy in Leishmania: alternative genetics. Trends Parasitol. 2014;30:429-35.
  15. Sterkers Y, et al. Novel insights into genome plasticity in eukaryotes: mosaic aneuploidy in Leishmania. Mol Microbiol. 2012;86:15-23.
  16. Niu O, et al. Iron acquisition in Leishmania and its crucial role in infection. Parasitol. 2016;143:1347-1357.
  17. Ubeda J, et al. Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol. 2008;9:115.
  18. Mannaert A, et al. Adaptive mechanisms in pathogens universal aneuploidy in Leishmania. Trends Parasitol. 2012;28:370-6.
  19. Dumetz F, et al. Modulation of aneuploidy in Leishmania donovani during adaptation to different in vitro and in vivo environments and its impact on gene expression. mBio. 2017;8:e.599-17.
  20. Rogers MB, et al. Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania. Genome Res. 2011;21:29-2142.
  21. Cardoso de Paiva RM, et al. Amastin knockdown in Leishmania braziliensis affects parasite-macrophage interaction and results in impaired viability of intracellular amastigotes. PLOS Pathogen. 2015;11:e.1005296.
  22. Laffitte MN, et al. Plasticity of the Leishmania genome leading to gene copy number variations and drug resistance. F1000 Res. 2016;55:2350.
  23. Cai M, et al. inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate-resistant colon cancer cells. Int J Cancer. 2019;144:1037-48.
  24. Kelso AA, et al. Homologous recombination in protozoan parasites and recombinase inhibitors. Front Microbiol. 2017;8:1716.
  25. Gilbert IH. Inhibitors of dihydrofolate reductase in leishmania and trypanosomes. Biochim Biophys Acta. 2002;1587:249-57.
  26. Kheirandish F, et al. Inhibition of Leishmania major PTR1 gene expression by antisense in Escherichia coli. Iran J Public Health. 2012;41:65-71. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468993/ [Accessed 15 January 2020]
  27. Cowan DSM, Tannock IF. Factors that influence the penetration of methotrexate through solids tissue. Int J Cancer. 2000;91:120-5.
  28. Monte-Neto R, et al. Intrachromosomal amplification, locus deletion and point mutation in the aquaglyceroporin AQP1 gene in antimony resistant Leishmania [viannia] guyanesis. PLoS Negl Trop Dis. 2015;9:e.0003476.
  29. Patino LH, et al. Genomic diversification, structural plasticity, and hybridization in Leishmania (Viannia) braziliensis. Front Cellular Infect Microbiol. 2020;20:e.582192.
  30. Lantorno SA, et al. Gene expression in Leishmania is regulated predominantly by gene dosage. mBio. 2017;8:e.1393-17.
  31. Damasceno JD, et al. Conditional knockout of RAD51-related genes in Leishmania major reveals a critical role for homologous recombination during genome replication. PLOS Genet. 2020;16:e1008828.
  32. Clayton C. Regulation of gene expression in trypanosomatids: living with polycistronic transcription. Open Biol. 2019;9:e.190072.
  33. Kieft R, et al. Identification of a novel base J binding protein complex involved in RNA polymerase II transcription termination in trypanosomes. PLOS Genet. 2020;16:e.1008390.
  34. Brewer-Jensen P, et al. Suppressor of sable [Su(s)] and Wrd82 down-regulate RNA from heat-shock-inducible repetitive elements by a mechanism that involves transcription termination. RNA. 2015;22:139-54.
  35. Damasceno JD, et al. Genome duplication in Leishmania major relies on persistent subtelomeric DNA replication. Elife. 2020;9:e58030.
  36. Mannaert A, et al. Adaptive mechanisms in pathogens: Universal aneuploidy in Leishmania. Trends Parasitol. 2012;28:370-76.
  37. Laffitte MN, et al. Chromosomal translocations in the parasite Leishmania MRE11/RAD50-independent microhomology-mediated joining mechanism. PLOS Genet. 2016;12:e1006117.
  38. Laffitte MN, et al. Formation of linear amplicons with inverted duplications in Leishmania requires the MRE11 nuclease. PLOS Genet. 2014;10:e1004805.
  39. Lamarche BJ, et al. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett. 2010;584:3682-95.
  40. Damasceno JD, et al. Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania. Nucleic Acids Res [e-journal]. 2018;46:11835-46.

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