Metabolic QTL Analysis Links Chloroquine Resistance in to Impaired Hemoglobin Catabolism

English version České info

Drug resistant strains of the malaria parasite, Plasmodium falciparum, have rendered chloroquine ineffective throughout much of the world. In parts of Africa and Asia, the coordinated shift from chloroquine to other drugs has resulted in the near disappearance of chloroquine-resistant (CQR) parasites from the population. Currently, there is no molecular explanation for this phenomenon. Herein, we employ metabolic quantitative trait locus mapping (mQTL) to analyze progeny from a genetic cross between chloroquine-susceptible (CQS) and CQR parasites. We identify a family of hemoglobin-derived peptides that are elevated in CQR parasites and show that peptide accumulation, drug resistance, and reduced parasite fitness are all linked in vitro to CQR alleles of the P. falciparum chloroquine resistance transporter (pfcrt). These findings suggest that CQR parasites are less fit because mutations in pfcrt interfere with hemoglobin digestion by the parasite. Moreover, our findings may provide a molecular explanation for the reemergence of CQS parasites in wild populations.

Vyšlo v časopise: Metabolic QTL Analysis Links Chloroquine Resistance in to Impaired Hemoglobin Catabolism. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004085
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004085

Souhrn

Zdroje

1. VestergaardLS, RingwaldP (2007) Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies. Am J Trop Med Hyg 77 : 153–159.

2. KublinJG, CorteseJF, NjunjuEM, MukadamRA, WirimaJJ, et al. (2003) Reemergence of chloroquine-sensitive plasmodium falciparum malaria after cessation of chloroquine use in malawi. J Infect Dis 187 : 1870–1875.

3. LiuDQ, LiuRJ, RenDX, GaoDQ, ZhangCY, et al. (1995) Changes in the resistance of plasmodium falciparum to chloroquine in hainan, china. Bull World Health Organ 73 : 483–486.

4. BURGESSRW, YOUNGMD (1959) The development of pyrimethamine resistance by plasmodium falciparum. Bull World Health Organ 20 : 37–46.

5. FidockDA, NomuraT, TalleyAK, CooperRA, DzekunovSM, et al. (2000) Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6 : 861–871.

6. CooperRA, FerdigMT, SuXZ, UrsosLM, MuJ, et al. (2002) Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in plasmodium falciparum. Mol Pharmacol 61 : 35–42.

7. WoottonJC, FengX, FerdigMT, CooperRA, MuJ, et al. (2002) Genetic diversity and chloroquine selective sweeps in plasmodium falciparum. Nature 418 : 320–323.

8. ChenN, KyleDE, PasayC, FowlerEV, BakerJ, et al. (2003) Pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant plasmodium falciparum isolates from the philippines. Antimicrob Agents Chemother 47 : 3500–3505.

9. Best PlummerW, Pinto PereiraLM, CarringtonCV (2004) Pfcrt and pfmdr1 alleles associated with chloroquine resistance in plasmodium falciparum from guyana, south america. Mem Inst Oswaldo Cruz 99 : 389–392.

10. DurrandV, BerryA, SemR, GlaziouP, BeaudouJ, et al. (2004) Variations in the sequence and expression of the plasmodium falciparum chloroquine resistance transporter (pfcrt) and their relationship to chloroquine resistance in vitro. Mol Biochem Parasitol 136 : 273–285.

11. SidhuAB, Verdier-PinardD, FidockDA (2002) Chloroquine resistance in plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 : 210–213.

12. MartinRE, KirkK (2004) The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Mol Biol Evol 21 : 1938–1949.

13. HaywardR, SalibaKJ, KirkK (2005) pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in plasmodium falciparum. Mol Microbiol 55 : 1285–1295.

14. ReedMB, SalibaKJ, CaruanaSR, KirkK, CowmanAF (2000) Pgh1 modulates sensitivity and resistance to multiple antimalarials in plasmodium falciparum. Nature 403 : 906–909.

15. BrayPG, MartinRE, TilleyL, WardSA, KirkK, et al. (2005) Defining the role of PfCRT in plasmodium falciparum chloroquine resistance. Mol Microbiol 56 : 323–333.

16. RajDK, MuJ, JiangH, KabatJ, SinghS, et al. (2009) Disruption of a plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. J Biol Chem 284 : 7687–7696.

17. KeurentjesJJ, FuJ, de VosCH, LommenA, HallRD, et al. (2006) The genetics of plant metabolism. Nat Genet 38 : 842–849.

18. KeurentjesJJ (2009) Genetical metabolomics: Closing in on phenotypes. Curr Opin Plant Biol 12 : 223–230.

19. Ranford-CartwrightLC, MwangiJM (2012) Analysis of malaria parasite phenotypes using experimental genetic crosses of plasmodium falciparum. Int J Parasitol 42 : 529–534.

20. SuX, FerdigMT, HuangY, HuynhCQ, LiuA, et al. (1999) A genetic map and recombination parameters of the human malaria parasite plasmodium falciparum. Science 286 : 1351–1353.

21. GonzalesJM, PatelJJ, PonmeeN, JiangL, TanA, et al. (2008) Regulatory hotspots in the malaria parasite genome dictate transcriptional variation. PLoS Biol 6: e238.

22. Reilly AyalaHB, WackerMA, SiwoG, FerdigMT (2010) Quantitative trait loci mapping reveals candidate pathways regulating cell cycle duration in plasmodium falciparum. BMC Genomics 11 : 577.

23. HaytonK, GaurD, LiuA, TakahashiJ, HenschenB, et al. (2008) Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of plasmodium falciparum invasion. Cell Host Microbe 4 : 40–51.

24. PatelJJ, ThackerD, TanJC, PleeterP, CheckleyL, et al. (2010) Chloroquine susceptibility and reversibility in a plasmodium falciparum genetic cross. Mol Microbiol 78 : 770–787.

25. SuX, HaytonK, WellemsTE (2007) Genetic linkage and association analyses for trait mapping in plasmodium falciparum. Nat Rev Genet 8 : 497–506.

26. TragerW, JensenJB (1976) Human malaria parasites in continuous culture. Science 193 : 673–675.

27. CuiQ, LewisIA, HegemanAD, AndersonME, LiJ, et al. (2008) Metabolite identification via the madison metabolomics consortium database. Nat Biotechnol 26 : 162–164.

28. WishartDS, TzurD, KnoxC, EisnerR, GuoAC, et al. (2007) HMDB: The human metabolome database. Nucleic Acids Res 35: D521–6.

29. BajadSU, LuW, KimballEH, YuanJ, PetersonC, et al. (2006) Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. J Chromatogr A 1125 : 76–88.

30. EckerA, LehaneAM, ClainJ, FidockDA (2012) PfCRT and its role in antimalarial drug resistance. Trends Parasitol 28 : 504–514.

31. LiuJ, IstvanES, GluzmanIY, GrossJ, GoldbergDE (2006) Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems. Proc Natl Acad Sci U S A 103 : 8840–8845.

32. GoldbergDE (2005) Hemoglobin degradation. Curr Top Microbiol Immunol 295 : 275–291.

33. GluzmanIY, FrancisSE, OksmanA, SmithCE, DuffinKL, et al. (1994) Order and specificity of the plasmodium falciparum hemoglobin degradation pathway. J Clin Invest 93 : 1602–1608.

34. BabbittSE, AltenhofenL, CobboldSA, IstvanES, FennellC, et al. (2012) Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state. Proc Natl Acad Sci U S A 109: E3278–87.

35. KrugliakM, ZhangJ, GinsburgH (2002) Intraerythrocytic plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins. Mol Biochem Parasitol 119 : 249–256.

36. LoriaP, MillerS, FoleyM, TilleyL (1999) Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials. Biochem J 339 (Pt 2) 363–370.

37. LewVL, TiffertT, GinsburgH (2003) Excess hemoglobin digestion and the osmotic stability of plasmodium falciparum-infected red blood cells. Blood 101 : 4189–4194.

38. PetersJM, ChenN, GattonM, KorsinczkyM, FowlerEV, et al. (2002) Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in plasmodium falciparum. Antimicrob Agents Chemother 46 : 2435–2441.

39. LauferMK, ThesingPC, EddingtonND, MasongaR, DzinjalamalaFK, et al. (2006) Return of chloroquine antimalarial efficacy in malawi. N Engl J Med 355 : 1959–1966.

40. ChenN, GaoQ, WangS, WangG, GattonM, et al. (2008) No genetic bottleneck in plasmodium falciparum wild-type pfcrt alleles reemerging in hainan island, china, following high-level chloroquine resistance. Antimicrob Agents Chemother 52 : 345.

41. SummersRL, NashMN, MartinRE (2012) Know your enemy: Understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics. Cell Mol Life Sci 69 : 1967–1995.

42. PatzewitzEM, Salcedo-SoraJE, WongEH, SethiaS, StocksPA, et al. (2012) Glutathione transport: A new role for PfCRT in chloroquine resistance. Antioxid Redox Signal 19 (7) 683–95.

43. MaughanSC, PasternakM, CairnsN, KiddleG, BrachT, et al. (2010) Plant homologs of the plasmodium falciparum chloroquine-resistance transporter, PfCRT, are required for glutathione homeostasis and stress responses. Proc Natl Acad Sci U S A 107 : 2331–2336.

44. ChiangCS, StaceyG, TsayYF (2004) Mechanisms and functional properties of two peptide transporters, AtPTR2 and fPTR2. J Biol Chem 279 : 30150–30157.

45. LehaneAM, HaywardR, SalibaKJ, KirkK (2008) A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites. J Cell Sci 121 : 1624–1632.

46. StennickeHR, SalvesenGS (1997) Biochemical characteristics of caspases-3, -6, -7, and -8. J Biol Chem 272 : 25719–25723.

47. ChughM, SundararamanV, KumarS, ReddyVS, SiddiquiWA, et al. (2013) Protein complex directs hemoglobin-to-hemozoin formation in plasmodium falciparum. Proc Natl Acad Sci U S A 110 : 5392–5397.

48. KamkumoRG, NgoutaneAM, TchokouahaLR, FokouPV, MadiesseEA, et al. (2012) Compounds from sorindeia juglandifolia (anacardiaceae) exhibit potent anti-plasmodial activities in vitro and in vivo. Malar J 11 : 382-2875-11-382.

49. DluzewskiAR, LingIT, RangachariK, BatesPA, WilsonRJ (1984) A simple method for isolating viable mature parasites of plasmodium falciparum from cultures. Trans R Soc Trop Med Hyg 78 : 622–624.

50. OlszewskiKL, MorriseyJM, WilinskiD, BurnsJM, VaidyaAB, et al. (2009) Host-parasite interactions revealed by plasmodium falciparum metabolomics. Cell Host Microbe 5 : 191–199.

51. SenS, ChurchillGA (2001) A statistical framework for quantitative trait mapping. Genetics 159 : 371–387.

52. ZeegersM, RijsdijkF, ShamP (2004) Adjusting for covariates in variance components QTL linkage analysis. Behav Genet 34 : 127–133.

53. ChurchillGA, DoergeRW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138 : 963–971.

54. StoreyJD, TibshiraniR (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 : 9440–9445.

55. BromanKW, WuH, SenS, ChurchillGA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19 : 889–890.

56. ClasquinMF, MelamudE, RabinowitzJD (2012) LC-MS data processing with MAVEN: A metabolomic analysis and visualization engine. Curr Protoc Bioinformatics Chapter 14: Unit14.11.