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Plasmodium vivax dhfr Mutations among Isolates from Malarious Areas of Iran

  • Received : 2010.10.17
  • Accepted : 2011.04.05
  • Published : 2011.06.30

Abstract

The use of sulfadoxine and pyrimethamine (SP) for treatment of vivax malaria is uncommon in most malarious areas, but Plasmodium vivax isolates are exposed to SP because of mixed infections with other Plasmodium species. As P. vivax is the most prevalent species of human malaria parasites in Iran, monitoring of resistance of the parasite against the drug is necessary. In the present study, 50 blood samples of symptomatic patients were collected from 4 separated geographical regions of south-east Iran. Point mutations at residues 57, 58, 61, and 117 were detected by the PCR-RFLP method. Polymorphism at positions 58R, 117N, and 117T of P. vivax dihydrofolate reductase (Pvdhfr) gene has been found in 12%, 34%, and 2% of isolates, respectively. Mutation at residues F57 and T61 was not detected. Five distinct haplotypes of the Pvdhfr gene were demonstrated. The 2 most prevalent haplotypes were F57S58T61S117 (62%) and F57S58T61N117 (24%). Haplotypes with 3 and 4 point mutations were not found. The present study suggested that P. vivax in Iran is under the pressure of SP and the sensitivity level of the parasite to SP is diminishing and this fact must be considered in development of malaria control programs.

Keywords

References

  1. Mendis K, Sina BJ, Marchesini P, Carter R. The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg 2001; 64: 97-106. https://doi.org/10.4269/ajtmh.2001.64.97
  2. Schousboe ML, Rajakaruna RS, Salanti A, Hapuarachchi HC, Galappaththy GN, Bygbjerg IC, Amerasinghe PH, Konradsen F, Alifrangis M. Island-wide diversity in single nucleotide polymorphisms of the Plasmodium vivax dihydrofolate reductase and dihydropteroate synthetase genes in Sri Lanka. Malar J 2007; 6: 28. https://doi.org/10.1186/1475-2875-6-28
  3. Auliff A, Wilson DW, Russell B, Gao Q, Chen N, Anh le N, Maquire J, Bell D, O'Neil MT, Cheng Q. Amino acid mutations in Plasmodium vivax DHFR and DHPS from several geographical regions and susceptibility to antifolate drugs. Am J Trop Med Hyg 2006; 75: 617-621.
  4. Kaur S, Prajapati SK, Kalyanaraman K, Mohmmed A, Joshi H, Chauhan VS. Plasmodium vivax dihydrofolate reductase point mutations from the Indian subcontinent. Acta Trop 2006; 97: 174-180. https://doi.org/10.1016/j.actatropica.2005.10.003
  5. Pukrittayakamee S, Imwong M, Looareesuwan S, White NJ. Therapeutic responses to antimalarial and antibacterial drugs in vivax malaria. Acta Trop 2004; 89: 351-356. https://doi.org/10.1016/j.actatropica.2003.10.012
  6. Gregson A, Plowe CV. Mechanism of resistance of malaria parasites to antifolates. Pharmacol Rev 2005; 57: 117-145. https://doi.org/10.1124/pr.57.1.4
  7. Alam MT, Bora H, Bharti PK, Saifi MA, Das MK, Dev V, Kumar A, Singh N, Dash AP, Das B, Wajihullah, Sharma YD. Similar trends of pyrimethamine resistance-associated mutations in Plasmodium vivax and P. falciparum. Antimicrob Agents Chemother 2007; 51: 857-863. https://doi.org/10.1128/AAC.01200-06
  8. Foote SJ, Cowman AF. The mode of action and the mechanism of resistance to antimalarial drugs. Acta Trop 1994; 56: 157-171. https://doi.org/10.1016/0001-706X(94)90061-2
  9. Thaithong S, Chan SW, Songsomboon S, Wilairat P, Seesod N, Sueblinwong T, Goman M, Ridley R, Beale G. Pyrimethamine resistant mutations in Plasmodium falciparum. Mol Biochem Parasitol 1992; 52: 149-158. https://doi.org/10.1016/0166-6851(92)90047-N
  10. Volz KW, Matthews DA, Alden RA, Freer ST, Hansch C, Kaufman BT, Kraut J. Crystal structure of avian dihydrofolate reductase containing phenyltriazine and NADPH. J Biol Chem 1982; 257: 2528-2536.
  11. Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci USA 1990; 87: 3018-3022. https://doi.org/10.1073/pnas.87.8.3018
  12. Zakeri S, Motmaen SR, Afsharpad M, Djadid ND. Molecular characterization of antifolates resistance-associated genes (dhfr and dhps) in Plasmodium vivax isolates from the Middle East. Malar J 2009; 8: 20. https://doi.org/10.1186/1475-2875-8-20
  13. de Pecoulas PE, Tahar R, Ouatas T, Mazabraud A, Basco LK. Sequence variations in the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene and their relationship with pyrimethamine resistance. Mol Biochem Parasitol 1998; 92: 265-273. https://doi.org/10.1016/S0166-6851(97)00247-8
  14. Hastings MD, Porter KM, Maquire JD, Susanti I, Kania W, Bangs MJ, Sibley CH, Baird JK. Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine. J Infect Dis 2004; 189: 744-750. https://doi.org/10.1086/381397
  15. Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 2002; 185: 380-388. https://doi.org/10.1086/338566
  16. Zakeri S, Najafabadi ST, Zare A, Djadid ND. Detection of malaria parasites by nested PCR in south-eastern, Iran: evidence of highly mixed infections in Chahbahar district. Malar J 2002; 1: 2. https://doi.org/10.1186/1475-2875-1-2
  17. Snounou G, White NJ. The co-existence of Plasmodium: sidelights from falciparum and vivax malaria in Thailand. Trends Parasitol 2004; 20: 333-339. https://doi.org/10.1016/j.pt.2004.05.004
  18. Imwong M, Pukrittakayamee S, Looareesuwan S, Pasvol G, Poirreiz J, White NJ, Snounou G. Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates. Antimicrob Agents Chemother 2001; 45: 3122-3127. https://doi.org/10.1128/AAC.45.11.3122-3127.2001
  19. Imwong M, Pukrittayakamee S, Renia L, Letourneur F, Charlieu JP, Leartsakulpanich U, Looareesuwan S, White NJ, Snounou G. Novel point mutations in the dihydrofolate reductase gene of Plasmodium vivax: evidence for sequential selection by drug pressure. Antimicrob Agents Chemother 2003; 47: 1514-1521. https://doi.org/10.1128/AAC.47.5.1514-1521.2003
  20. Tjitra E, Baker J, Suprianto S, Cheng Q, Anstey NM. Therapeutic efficacies of artesunate-sulfadoxine-pyrimethamine and chloroquine-sulfadoxine-pyrimethamine in vivax malaria pilot studies: relationship to Plasmodium vivax dhfr mutations. Antimicrob Agents Chemother 2002; 46: 3947-3953. https://doi.org/10.1128/AAC.46.12.3947-3953.2002
  21. Hastings MD, Maguire JD, Bangs MJ, Zimmerman PA, Reeder JC, Baird JK, Sibley CH. Novel Plasmodium vivax dhfr alleles from the Indonesian Archipelago and Papua New Guinea: association with pyrimethamine resistance determined by a Saccharomyces cerevisiae expression system. Antimicrob Agents Chemother 2005; 49: 733-740. https://doi.org/10.1128/AAC.49.2.733-740.2005
  22. Brega S, de Monbrison F, Severini C, Udomsangpetch R, Sutanto I, Ruckert P, Peyron F, Picot S. Real-time PCR for dihydrofolate reductase gene single-nucleotide polymorphisms in Plasmodium vivax isolates. Antimicrob Agents Chemother 2004; 48: 2581-2587. https://doi.org/10.1128/AAC.48.7.2581-2587.2004
  23. de Pecoulas PE, Tahar R, Yi P, Thai KH, Basco LK. Genetic variation of the dihydrofolate reductase gene in Plasmodium vivax in Snoul, northeastern Cambodia. Acta Trop 2004; 92: 1-6. https://doi.org/10.1016/j.actatropica.2004.03.011
  24. Na BK, Lee HW, Moon SU, In TS, Lin K, Maung M, Chung GT, Lee JK, Kim TS, Kong Y. Genetic variations of the dihydrofolate reductase gene of Plasmodium vivax in Mandalay Division, Myanmar. Parasitol Res 2005; 96: 321-325. https://doi.org/10.1007/s00436-005-1364-0
  25. Schunk M, Kumma WP, Miranda IB, Osman ME, Roewer S, Alano A, Loscher T, Bienzle U, Mockenhaupt FP. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in Southern Ethiopia. Malar J 2006; 5: 54-59. https://doi.org/10.1186/1475-2875-5-54
  26. Valecha N, Joshi H, Eapen A, Ravinderan J, Kumar A, Prajapati SK, Ringwald P. Therapeutic efficacy of chloroquine in Plasmodium vivax from areas with different epidemiological patterns in India and their Pvdhfr gene mutation pattern. Trans R Soc Trop Med Hyg 2006; 100: 831-837. https://doi.org/10.1016/j.trstmh.2005.11.012
  27. Leartsakulpanich U, Imwong M, Pukrittayakamee S, White NJ, Snounou G, Sirawaraporn W, Yuthavong Y. Molecular characterization of dihydrofolate reductase in relation to antifolate resistance in Plasmodium vivax. Mol Biochem Parasitol 2002; 119: 63-73. https://doi.org/10.1016/S0166-6851(01)00402-9
  28. Tahar R, de Pecoulas PE, Basco LK, Chiadmi M, Mazabraud A. Kinetic properties of dihydrofolate reductase from wild-type and mutant Plasmodium vivax expressed in Escherichia coli. Mol Biochem Parasitol 2001; 113: 241-249. https://doi.org/10.1016/S0166-6851(01)00230-4
  29. Diseases Management Center of MOH, I.R. Iran. Annual Reports of Malaria. 2006.
  30. Shahbazi A, Raeisi A, Nateghpour M,Mirhendi H, Mohebali M, Asmar M. Polymorphism of merozoite surface protein-$3\alpha$ gene of Plasmodium vivax in isolates of Iran. Iran J Parasitol 2008; 3: 15-20.
  31. Shahbazi A, Raeisi A, Nateghpour M, Mirhendi H, Mohebali M, Asmar M. Diversity of merozoite surface protein-$3\beta$ gene of Plasmodium vivax isolates from Iran. Iran J Public Health 2007; 36: 1-5
  32. Snounou G, Pinheiro L, Goncalves A, Fonseca L, Dias F, Brown KN, Rosario VE. The importance of sensitive detection of malaria parasites in the human and insect hosts in epidemiological studies, as shown by the analysis of field samples from Guinea Bissau. Trans R Soc Trop Med Hyg 1993; 87: 649-653. https://doi.org/10.1016/0035-9203(93)90274-T
  33. Hawkins VN, Joshi H, Rungsihirunrat K, Na-Bangchang K, Sibley CH. Antifolates can have a role in the treatment of Plasmodium vivax. Trends Parasitol 2007; 23: 213-222. https://doi.org/10.1016/j.pt.2007.03.002
  34. Imwong M, Pukrittayakamee S, Cheng Q, Moore C, Looareesuwan S, Snounou G, White NJ, Day NP. Limited Polymorphism in the dihydropteroate synthetase gene (dhps) of Plasmodium vivax isolates from Thailand. Antimicrob Agents Chemother 2005; 49: 4393-4395. https://doi.org/10.1128/AAC.49.10.4393-4395.2005

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  1. MOLECULAR SURVEILLANCE OF Plasmodium vivax AND Plasmodium falciparum DHFR MUTATIONS IN ISOLATES FROM SOUTHERN IRAN vol.58, pp.58, 2011, https://doi.org/10.1590/s1678-9946201658016
  2. Mutational Analysis of Plasmodium vivax dhfr Gene Among Cases in South East of Iran vol.10, pp.9, 2017, https://doi.org/10.5812/jjm.57697