Functional Analysis of Plasmodium Falciparum Subpopulations Associated with Artemisinin Resistance in Cambodia

Overview

Journal Malar J

Publisher Biomed Central

Specialty Tropical Medicine

Date 2017 Dec 21

PMID 29258508

Citations 12

Authors

Ankit Dwivedi

Christelle Reynes

Axel Kuehn

Daniel B Roche

Nimol Khim

Maxim Hebrard

Sylvain Milanesi

Eric Rivals

Roger Frutos

Didier Menard

Choukri Ben Mamoun

Jacques Colinge

Emmanuel Cornillot

Affiliations

Soon will be listed here.

Abstract

Background: Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008-2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs.

Results: Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population.

Conclusions: Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations.

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References

Ashley E, Dhorda M, Fairhurst R, Amaratunga C, Lim P, Suon S . Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014; 371(5):411-23. PMC: 4143591. DOI: 10.1056/NEJMoa1314981. View

Dondorp A, Nosten F, Yi P, Das D, Phyo A, Tarning J . Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009; 361(5):455-67. PMC: 3495232. DOI: 10.1056/NEJMoa0808859. View

Spitzmuller A, Mestres J . Prediction of the P. falciparum target space relevant to malaria drug discovery. PLoS Comput Biol. 2013; 9(10):e1003257. PMC: 3798273. DOI: 10.1371/journal.pcbi.1003257. View

Wu S, Zhang Y . LOMETS: a local meta-threading-server for protein structure prediction. Nucleic Acids Res. 2007; 35(10):3375-82. PMC: 1904280. DOI: 10.1093/nar/gkm251. View

Miotto O, Almagro-Garcia J, Manske M, MacInnis B, Campino S, Rockett K . Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet. 2013; 45(6):648-55. PMC: 3807790. DOI: 10.1038/ng.2624. View

Kelley L, Mezulis S, Yates C, Wass M, Sternberg M . The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015; 10(6):845-58. PMC: 5298202. DOI: 10.1038/nprot.2015.053. View

Amaratunga C, Witkowski B, Khim N, Menard D, Fairhurst R . Artemisinin resistance in Plasmodium falciparum. Lancet Infect Dis. 2014; 14(6):449-50. PMC: 4573664. DOI: 10.1016/S1473-3099(14)70777-7. View

Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois A, Khim N . A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2013; 505(7481):50-5. PMC: 5007947. DOI: 10.1038/nature12876. View

Bray P, Martin R, Tilley L, Ward S, Kirk K, Fidock D . Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Mol Microbiol. 2005; 56(2):323-33. DOI: 10.1111/j.1365-2958.2005.04556.x. View

10.

Lee D, Seung H . Learning the parts of objects by non-negative matrix factorization. Nature. 1999; 401(6755):788-91. DOI: 10.1038/44565. View

11.

Paloque L, Ramadani A, Mercereau-Puijalon O, Augereau J, Benoit-Vical F . Plasmodium falciparum: multifaceted resistance to artemisinins. Malar J. 2016; 15:149. PMC: 4784301. DOI: 10.1186/s12936-016-1206-9. View

12.

Briolant S, Bogreau H, Gil M, Bouchiba H, Baret E, Amalvict R . The F423Y mutation in the pfmdr2 gene and mutations N51I, C59R, and S108N in the pfdhfr gene are independently associated with pyrimethamine resistance in Plasmodium falciparum isolates. Antimicrob Agents Chemother. 2012; 56(5):2750-2. PMC: 3346656. DOI: 10.1128/AAC.05618-11. View

13.

Menard D, Khim N, Beghain J, Adegnika A, Shafiul-Alam M, Amodu O . A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms. N Engl J Med. 2016; 374(25):2453-64. PMC: 4955562. DOI: 10.1056/NEJMoa1513137. View

14.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

15.

Shannon P, Markiel A, Ozier O, Baliga N, Wang J, Ramage D . Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-504. PMC: 403769. DOI: 10.1101/gr.1239303. View

16.

Payne D . Did medicated salt hasten the spread of chloroquine resistance in Plasmodium falciparum?. Parasitol Today. 1988; 4(4):112-5. DOI: 10.1016/0169-4758(88)90042-7. View

17.

Manske M, Miotto O, Campino S, Auburn S, Almagro-Garcia J, Maslen G . Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature. 2012; 487(7407):375-9. PMC: 3738909. DOI: 10.1038/nature11174. View

18.

Zhang S, Feng J, Cao Y, Meng L, Wang S . Autophagy prevents autophagic cell death in Tetrahymena in response to oxidative stress. Dongwuxue Yanjiu. 2015; 36(3):167-73. PMC: 4790692. View

19.

Phimda K, Hoontrakul S, Suttinont C, Chareonwat S, Losuwanaluk K, Chueasuwanchai S . Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus. Antimicrob Agents Chemother. 2007; 51(9):3259-63. PMC: 2043199. DOI: 10.1128/AAC.00508-07. View

20.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View