1921
Volume 78, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

This study was designed to analyze the resistance transporter () and multidrug resistance 1 () mutations as markers of chloroquine (CQ) resistance in 200 blood samples collected from malaria patients in south-eastern Iran during 2002–2005. Among these, 25 (post-treatment) fulfilled the 28-day follow-up study. A high number of Iranian (97%) strains harbored quadruple mutations at codons 76T, 220S, 326D, and 356L. All post-treatment isolates harbored the mutant allele 76T, but low rates of the mutant allele 86Y (44%) of the gene were detected. No wild haplotype of (72-CVMNKAQNIR-371) was found in post-treatment samples; however, 56% of clinical “failure” samples carried the wild type of (NYSND). The present results suggest a strong association between 76T, but not 86Y mutation and CQ resistance. Furthermore, we found the CQ resistance-associated SVMNT haplotype, which previously had been seen in South American isolates. Although Iran is located more proximally to Southeast Asia than to South America, no CQ resistance-associated CVIET haplotye has been observed in this region. Therefore, these results were not consistent with the earlier presumed spread of CQR parasites from Southeast Asia to Africa via the Indian subcontinent. In conclusion, mutations associated with resistance to CQ are abundant in south-eastern Iran and this finding strongly supports that CQ as the first line drug is inadequate for treatment of uncomplicated falciparum malaria in Iran.

Loading

Article metrics loading...

/content/journals/10.4269/ajtmh.2008.78.633
2008-04-01
2017-11-20
Loading full text...

Full text loading...

/deliver/fulltext/14761645/78/4/0780633.html?itemId=/content/journals/10.4269/ajtmh.2008.78.633&mimeType=html&fmt=ahah

References

  1. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2 : 209–218.
  2. Misra SP, 1996. In vivo resistance to chloroquine and sulfadoxine/pyrimethamine combination in Plasmodium falciparum in India. Proc Nat Acad Sci India 66 : 123–128.
  3. Sharma YD, Biswas S, Pillai CR, Ansari MA, Adak T, Devi U, 1996. High prevalence of chloroquine resistant Plasmodium falciparum infection in Rajasthan epidemic. Acta Trop 62 : 135–141.
  4. Edrissian GH, Shahabi S, Pishva E, Hajseyed-Javadi J, Khaleghian B, Ghorbani M, Emadi AM, Afshar A, Saghari H, 1986. Imported cases of chloroquine-resistant falciparum malaria in Iran. Bull Soc Pathol Exot 79 : 217–221.
  5. Edrissian GH, Nateghpour M, Afshar A, Sayedzadeh A, Mohsseni GH, Satvat MT, Emadi AM, 1999. Monitoring the response of P. falciparum and P. vivax to anti malarial drugs in the malarious areas in south-east Iran. Arch Iran Med 2 : 61–66.
  6. Raeisi A, Ringwald P, Safa O, Shahbazi A, Ranjbar M, Keshavarze H, Nateghpour M, Faraji L, 2006. Monitoring of the therapeutic efficacy of chloroquine for the treatment of uncomplicated, Plasmodium falciparum malaria in Iran. Ann Trop Med Parasitol 100 : 11–16.
  7. Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LMB, Sidhu AB, Naude B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE, 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6 : 861–871.
  8. Su X, Kirkman LA, Fujioka H, Wellems TE, 1997. Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant Plasmodium falciparum in Southeast Asia and Africa. Cell 91 : 593–603.
  9. Martin SK, Oduola AMJ, Milhous WK, 1987. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235 : 899–901.
  10. Wilson CM, Serrano AE, Wasley A, Bogenschutz MP, Shankar AH, Wirth DF, 1989. Amplification of a gene related to mammalian mdr genes in drug resistant Plasmodium falciparum. Science 244 : 1184–1186.
  11. Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF, 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345 : 255–258.
  12. Fidock DA, Nomura T, Cooper RA, Su X, Talley AK, Wellems E, 2000. Allelic modifications of cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum. Mol Biochem Parasitol 110 : 1–10.
  13. Awad-el-Kariem FM, Miles MA, Warhurst DC, 1992. Chloroquine-resistant Plasmodium falciparum isolates from the Sudan lack two mutations in the pfmdrl gene thought to be associated with chloroquine resistance. Trans R Soc Trop Med Hyg 86 : 587–589.
  14. Wellems TE, Walker-Jonah A, Panton LJ, 1991. Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc Natl Acad Sci USA 88 : 3382–3386.
  15. Basco LK, Ringwald P, 2002. Molecular epidemiology of malaria in Cameroon. X. Evolution of pfmdr1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives. Am J Trop Med Hyg 66 : 667–671.
  16. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, 2000. Pgh1 modulates sensitivity and resistance to multiple anti-malarials in Plasmodium falciparum. Nature 403 : 906–909.
  17. Cowman AF, 1991. The P-glycoprotein homologs of Plasmodium falciparum: are they involved in chloroquine resistance? Parasitol Today 7 : 70–76.
  18. Schneider AG, Premji Z, Feleger I, 2002. A point mutation in codon 76 of pfcrt of P. falciparum is positively selected for by chloroquine resistance in Tanzania. Infect Genet Evol 1 : 183–189.
  19. Pillai DR, Hijar G, Montoya Y, 2003. Lack of prediction of mefloquine and mefloquine– artesunate treatment outcome by mutation in Plasmodium falciparum multidrug resistance 1 (pfmdr 1) gene for P. falciparum malaria in Peru. Am J Trop Med Hyg 68 : 107–110.
  20. Huaman MC, Roncal N, Nakazawa S, Long TT, Gerena L, Garcia C, 2004. Polymorphism of the Plasmodium falciparum multidrug resistance and chloroquine resistance transporter genes and in vitro susceptibility to aminoquinolines in isolates from the Peruvian Amazon. Am J Trop Med Hyg 70 : 461–466.
  21. Pickard AL, Wongsrichanalai C, Purfield A, Kamwendo D, Emery K, Zalewski C, 2003. Resistance to anti-malarials in Southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob Agents Chemother 47 : 2418–2423.
  22. Price RN, Cassar C, Brockman A, Duraisingh M, Van-Vugt M, White NJ, Nosten F, Krishna S, 2004. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob Agents Chemother 43 : 2943–2949.
  23. Wellems TE, Plowe CV, 2001. Chloroquine-resistant malaria. J Infect Dis 184 : 770–776.
  24. Djimdé A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourté Y, Dicko A, Su X, Nomura T, Fidock DA, Wellems TE, Plowe CV, 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344 : 257–263.
  25. Durand R, Jafari S, Vauzelle J, Delabre JF, Jesic Z, Le Bras J, 2001. Analysis of pfcrt point mutations and chloroquine susceptibility in isolates of Plasmodium falciparum. Mol Biochem Parasitol 114 : 95–102.
  26. Sanchez C, Lanzer M, 2000. Changing ideas on chloroquine in Plasmodium falciparum. Curr Opin Infect Dis 13 : 653–658.
  27. Babiker HA, Pringle SJ, Abdel-Muhsin A, Mackinnon M, Hunt P, Walliker D, 2001. High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1. J Infect Dis 183 : 1535–1538.
  28. Mackinnon MJ, Hastings IM, 1998. The evolution of multiple drug resistance in malaria parasites. Trans R Soc Trop Med Hyg 92 : 188–195.
  29. Basco LK, Ringwald P, 1998. Molecular epidemiology of malaria in Yaounde, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr1) gene of Plasmodium falciparum. Am J Trop Med Hyg 59 : 577–581.
  30. Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ, 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418 : 320–323.
  31. Lim P, Chy S, Ariey F, Incardona S, Chim P, Sem R, Denis MB, Hewitt S, Hoyer S, Socheat D, Merecreau-Puijalon O, Fandeur T, 2003. pfcrt polymorphism and chloroquine resistance in Plasmodium falciparum strains isolated in Cambodia. Antimicrob Agents Chemother 47 : 87–94.
  32. Uhleman AC, Yuthavong Y, Fidock DA, 2005. Mechanisms of anti-malarial drug action and resistance. Sherman IW, ed. Molecular Approaches to Malaria. Washington, DC: ASM Press, 429–461.
  33. Chen N, Kyle DE, Pasay C, Fowler EV, Baker J, Peters JM, Cheng Q, 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.
  34. Durand V, Berry A, Sem R, Glaziou P, Beaudou J, Fandeur T, 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.
  35. Mehlotra RK, Fujioka H, Roepe PD, Janneh O, Ursos LM, Jacobs-Lorena V, McNamara DT, Bockarie MJ, Kazura JW, Kyle DE, Fidock DA, Zimmerman PA, 2001. Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc Natl Acad Sci USA 98 : 12689–12694.
  36. Chen N, Russell B, Staley J, Kotecka B, Nasveld P, Cheng Q, 2001. Sequence polymorphisms in pfcrt are strongly associated with chloroquine resistance in Plasmodium falciparum. J Infect Dis 183 : 1543–1545.
  37. Ursing J, Zakeri S, Gil JP, Bjorkman A, 2006. Quinoline resistance associated polymorphisms in the pfcrt, pfmdr1 and pfmrp genes of Plasmodium falciparum in Iran. Acta Trop 97 : 352–356.
  38. Zakeri S, Gil JP, Bereckzy S, Djadid ND, Bjorkman A, 2003. High prevalence of double Plasmodium falciparum dhfr mutations at codons 108 and 59 in the Sistan–Baluchistan province, Iran. J Infect Dis 187 : 1828–1829.
  39. Zakeri S, Najajabadi S, Zare A, Djadid N, 2002. Detection of malaria parasites by nested PCR in south-eastern, Iran: evidence of highly mixed infections in Chabahar district. Malar J 1 : 2.
  40. Heidari A, Dittrich S, Jelinek T, Kheirandish A, Banihashemi K, Keshavarz H, 2007. Genotypes and in vivo resistance of Plasmodium falciparum isolates in an endemic region of Iran. Parasitol Res 100 : 589–592.
  41. Jafari S, Le Bras J, Asmar M, Durand R, 2003. Molecular survey of Plasmodium falciparum resistance in south-eastern Iran. Ann Trop Med Parasitol 97 : 119–124.
  42. Wernsdorfer WH, Payne D, 1998. Drug sensitivity tests in malaria parasites. Wernsdorfer WH, MacGregor I, eds. Principles and Practice of Malariolology. London: Churchill Livingstone, 1765–1794.
  43. Snounou G, Zhu X, Siripoon N, Jarra W, Thaithong S, Brown KN, Viriyakosol S, 1999. Biased distribution of msp1 and msp2 allelic variants in Plasmodium falciparum populations in Thailand. Trans R Soc Trop Med Hyg 93 : 369–374.
  44. Snounou G, Viriyakosol S, Zhu XP, Jarra W, Pinheiro L, do Rosario VE, Thaithong S, Brown KN, 1993. High sensitivity of detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol 61 : 315–320.
  45. Duraisingh MT, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst DC, 2000. The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Mol Biochem Parasitol 108 : 13–23.
  46. University of Maryland Center for Vaccine Development. http://medschool.umaryland.edu/cvd/nejm2001djimde.asp.
  47. Purfield A, Nelson A, Laoboonchai A, Congpuong K, McDaniel P, Miller RS, Welch K, Wongsrichanalai C, Meshnick SR, 2004. A new method for detection of pfmdr1 mutations in Plasmodium falciparum DNA using real-time PCR. Malar J 7 : 91.
  48. Congpuong K, Bangchang KN, Mungthin M, Bualombai P, Wernsdorfer WH, 2005. Molecular epidemiology of drug resistance markers of Plasmodium falciparum malaria in Thailand. Trop Med Int Health 10 : 717–722.
  49. McCutcheon KRG, Freese JA, Frean JA, Sharp BL, Markus MB, 1999. Two mutations in the multidrug-resistance gene homologue of Plasmodium falciparum, pfmdr1, are not useful predictors of in vivo or in vitro chloroquine resistance in southern Africa. Trans R Soc Trop Med Hyg 93 : 300–302.
  50. Dorsey G, Kamya MR, Singh A, Rosenthal PJ, 2001. Polymorphisms in the Plasmodium falciparum pfcrt and pfmdr-1 genes and clinical response to chloroquine in Kampala, Uganda. J Infect Dis 183 : 1417–1420.
  51. Pillai DR, Labbe AC, Vanisaveth V, Hongvangthong B, Pomphida S, Inkathone S, 2001. Plasmodium falciparum malaria in Laos: chloroquine treatment outcome and predictive value of molecular markers. J Infect Dis 183 : 789–795.
  52. Zalis MG, Pang L, Silveira MS, Milhous WK, Wirth DF, 1998. Characterization of Plasmodium falciparum isolated from the Amazon region of Brazil: evidence for quinine resistance. Am J Trop Med Hyg 58 : 630–637.
  53. Nagesha HS, Casey GJ, Rieckmann KH, Fryauff DJ, Laksana BS, Reeder JC, Maguire JD, Baird JK, 2003. New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine resistant parasite isolates. Am J Trop Med Hyg 68 : 398–402.
  54. Plummer WB, Pereira LMP, Carrington CVF, 2004. pfcrt and pfmdr1 alleles associated with chloroquine resistance in Plasmodium falciparum from Guyana, South America. Mem Inst Oswaldo Cruz 99 : 389–392.
  55. Chen N, Wilson DW, Pasay C, Bell D, Martin LB, Kyle D, Cheng Q, 2005. Origin and dissemination of chloroquine-resistant Plasmodium falciparum with mutant pfcrt alleles in the Philippines. Antimicrob Agent Chemother 49 : 2102–2105.
  56. Vathsala PG, Pramanik A, Dhanasekaran S, Devi CU, Pillai CR, Subbarao SK, Ghosh SK, Tiwari SN, Sathyanarayan TS, Deshpande PR, Mishra GC, Ranjit MR, Dash AP, Rangarajan PN, Padmanaban G, 2004. Widespread occurrence of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT in P. falciparum malaria in India. Am J Trop Med Hyg 70 : 256–259.
  57. Alifrangis M, Dalgaad MB, Lusingu JP, Vestergaad LS, Staalsoe T, Jensen ATR, Enevold A, Ronn AM, Khalil IF, Warhurst DC, Lemnge MM, Theander TG, Bygbjerg C, 2006. Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania. J Infect Dis 193 : 1738–1741.
  58. Dittrich S, Alifrangis M, Stohrer MJ, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, Phompida S, Khalil IF, Jelinek T, 2005. Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT. Trop Med Int Health 10 : 1267–1270.
  59. Keen J, Farcas GA, Zhong K, Yohanna S, Dunne MW, Kain KC, 2007. Real time PCR assay for rapid detection and analysis of PFCRT haplotypes of chloroquine-resistant Plasmodium falciparum isolates from India. J Clin Microbiol 45 : 2889–2893.
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.2008.78.633
Loading
/content/journals/10.4269/ajtmh.2008.78.633
Loading

Data & Media loading...

  • Received : 19 May 2007
  • Accepted : 19 Nov 2007

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error