Alta frecuencia de mutaciones puntuales en pfcrt de Plasmodium falciparum y emergencia de nuevos haplotipos mutantes en Colombia
Keywords:
Plasmodium falciparum, malaria, antimalarials, chloroquine, mutation, Colombia
Abstract
Introduction. Studies on the molecular epidemiology of antimalarial resistance constitute a useful tool to understand the events underlying treatment failure and resistance in falciparum malaria in Colombia. Several authors have reported on the efficacy of some molecular markers to predict drug resistance in Plasmodium falciparum. The P. falciparum pfcrt gene has been widely characterized in this context.Objective. The frequency of pfcrt gene mutations in P. falciparum were associated with treatment failure to the antimalarials chloroquine, mefloquine, amodiaquine and sulfadoxine/ pyrimethamine.
Materials and methods. A representative sample of 172 patients with non-complicated falciparum malaria was selected from two highly malaria-endemic areas of northeastern Colombia, the Turbo and Bajo Cauca regions. These patients were assessed for treatment response together with the status of codons 72, 74, 75 and 76 in the pfcrt gene using a PCRRFLP approach.
Results. A high frequency of treatment failure to chloroquine (82%) and to amodiaquine (29%) was confirmed, whereas mefloquine and combined therapy remained effective. The presence of the T76 mutation in pfcrt was confirmed in all samples. The most common haplotype was CMNT (67%).
Conclusions. No significant association was confirmed between specific haplotypes and the treatment response in any of the treatment groups. Two haplotypes, SMET and SMNT, were reported for the first time in Colombia. Twelve percent of the samples carried both mixed mutant and wild-type alleles.
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References
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11. Djimde A, Doumbo OK, Steketee RW, Plowe CV. Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria. Lancet. 2001;358:890-1.
12. Howard EM, Zhang H, Roepe PD. A novel transporter, Pfcrt, confers antimalarial drug resistance. J Membr Biol. 2002;190:1-8.
13. Wernsdorfer WH, Noedl H. Molecular markers for drug resistance in malaria: use in treatment, diagnosis and epidemiology. Curr Opin Infect Dis. 2003;16:553-8.
14. OMS/OPS. Evaluación de la eficacia terapéutica de los medicamentos para el tratamiento del paludismo por Plasmodium falciparum sin complicaciones en las Américas. Washington D.C.: OPS/HCP/HCT/113/98; 1998.
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17. Dittrich S, Alifrangis M, Stohrer JM, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, et al. 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. 2005;10:1267-70.
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25. Nagesha HS, Din-Syafruddin, Casey GJ, Susanti AI, Fryauff DJ, Reeder JC, et al. Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in-vivo drug resistance in West Papua, Indonesia. Trans R Soc Trop Med Hyg. 2001;95:43-9.
26. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature. 2000;403:906-9.
27. Mita T, Kaneko A, Hombhanje F, Hwaihwanje I, Takahashi N, Osawa H, et al. Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea. Acta Trop. 2006;98:137-44.
28. Montoya P, Tobón A, Blair S, Carmona J, Maestre A. Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia. Biomédica. 2007;27:204-15.
29. Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, et al. Reemergence of chloroquine- sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis. 2003;187:1870-5.
30. Mita T, Kaneko A, Lum JK, Bwijo B, Takechi M, Zungu IL, et al. Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. Am J Trop Med Hyg. 2003;68:413-5.
31. Gonzalez IJ, Varela RE, Murillo C, Ferro BE, Salas J, Giraldo LE, et al. Polymorphisms in cg2 and pfcrt genes and resistance to chloroquine and other antimalarials in vitro in Plasmodium falciparum isolates from Colombia. Trans R Soc Trop Med Hyg. 2003;97:318-24.
32. Echeverry DF, Holmgren G, Murillo C, Higuita JC, Björkman A, Gil JP, et al. Polymorphisms in the pfcrt and pfmdr1 genes of Plasmodium falciparum and in vitro susceptibility to amodiaquine and desethylamodiaquine. Am J Trop Med Hyg. 2007;77:1034-8.
33. Vieira PP, Ferreira MU, Alecrim MG, Alecrim WD, da Silva LH, Sihuincha MM, et al. pfcrt polymorphism and the spread of chloroquine resistance in Plasmodium falciparum populations across the Amazon Basin. J Infect Dis. 2004;190:417-24.
34. Wootton JC. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature. 2002;418:320-3.
2. White NJ. Drug resistance in malaria. Br Med Bull. 1998;54:703-15.
3. Peters W. Drug resistance in malaria parasites of animals and man. Adv Parasitol. 1998;41:1-62.
4. Holmgren G, Gil JP, Ferreira PM, Veiga MI, Obonyo CO, Björkman A. Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect Gen Evol. 2006;6:309-14.
5. Ochong EO, van den Broek, Keus K, Nzila A. Association between chloroquine and amodiaquine resistance and allelic variation in the Plasmodium falciparum multiple drug resistance 1 gene and the chloroquine resistance transporter gene in isolates from the upper Nile in southern Sudan. Am J Trop Hyg. 2003;69:184-7.
6. Le Bras J, Durand R. The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum. Fundament Clin Pharmacol. 2003;17:147-53.
7. Congpuong K, Bangchang KN, Mungthin M, Bualombai P, Wernsdorfer WH. Molecular epidemiology of drug resistance markers of Plasmodium falciparum malaria in Thailand. Trop Med Int Health. 2005;10:717-22.
8. Mayengue PI, Ndounga M, Davy MM, Tandou N, Ntoumi F. In vivo chloroquine resistance and prevalence of the pfcrt codon 76 mutation in Plasmodium falciparum isolates from the Republic of Congo. Acta Trop. 2005;95:219-25.
9. Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science. 2002;298:210-3.
10. Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell. 2000;6:861-71.
11. Djimde A, Doumbo OK, Steketee RW, Plowe CV. Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria. Lancet. 2001;358:890-1.
12. Howard EM, Zhang H, Roepe PD. A novel transporter, Pfcrt, confers antimalarial drug resistance. J Membr Biol. 2002;190:1-8.
13. Wernsdorfer WH, Noedl H. Molecular markers for drug resistance in malaria: use in treatment, diagnosis and epidemiology. Curr Opin Infect Dis. 2003;16:553-8.
14. OMS/OPS. Evaluación de la eficacia terapéutica de los medicamentos para el tratamiento del paludismo por Plasmodium falciparum sin complicaciones en las Américas. Washington D.C.: OPS/HCP/HCT/113/98; 1998.
15. Singh B, Cox-Singh J, Miller AO, Abdullah MS, Snounou G, Rahman HA. Detection of malaria in Malaysia by nested polymerase chain reaction amplification of dried blood spots on filter papers. Trans R Soc Trop Med Hyg. 1996;90:519-21.
16. Blair S, Lopez ML, Piñeros JG, Alvarez T, Tobon A, Carmona J. Eficacia terapéutica de tres esquemas de tratamiento de malaria no complicada por Plasmodium falciparum, Antioquia, Colombia, 2002. Biomédica. 2003;23:318-27.
17. Dittrich S, Alifrangis M, Stohrer JM, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, et al. 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. 2005;10:1267-70.
18. Nsimba B, Jafari-Guemouri S, Malonga DA, Mouata AM, Kiori J, Louya F, et al. Epidemiology of drug resistant malaria in Republic of Congo: using molecular evidence for monitoring antimalarial drug resistance combined with assessment of antimalarial drug use. Trop Med Int Health. 2005;10:1030-7.
19. Basco LK, Le Bras J, Rhoades Z, Wilson CM. Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subSaharan Africa. Mol Biochem Parasitol. 1995;74:157-66.
20. Duraisingh MT, Drakeley CJ, Muller O,Bailey R, Snounou G, Targett GA, et al. Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine. Parasitology. 1997;114:205-11.
21. Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, et al. Several alleles of the multidrugresistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature. 1990; 345:255-8.
22. Grobusch MP, Adagu IS, Kremsner PG, Warhurst DC. Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon. Parasitology. 1998;116:211-7.
23. von Seidlein L, Duraisingh MT, Drakeley CJ, Bailey R, Greenwood BM, Pinder M. Polymorphism of the Pfmdr1 gene and chloroquine resistance in Plasmodium falciparum in The Gambia.Trans R Soc Trop Med Hyg. 1997;91:450-3.
24. Gomez-Saladin E, Fryauff DJ, Taylor WR, Laksana BS, Susanti AI, Purnomo, et al. Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia. Am J Trop Med Hyg. 1999;61:240-4.
25. Nagesha HS, Din-Syafruddin, Casey GJ, Susanti AI, Fryauff DJ, Reeder JC, et al. Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in-vivo drug resistance in West Papua, Indonesia. Trans R Soc Trop Med Hyg. 2001;95:43-9.
26. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature. 2000;403:906-9.
27. Mita T, Kaneko A, Hombhanje F, Hwaihwanje I, Takahashi N, Osawa H, et al. Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea. Acta Trop. 2006;98:137-44.
28. Montoya P, Tobón A, Blair S, Carmona J, Maestre A. Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia. Biomédica. 2007;27:204-15.
29. Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, et al. Reemergence of chloroquine- sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis. 2003;187:1870-5.
30. Mita T, Kaneko A, Lum JK, Bwijo B, Takechi M, Zungu IL, et al. Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. Am J Trop Med Hyg. 2003;68:413-5.
31. Gonzalez IJ, Varela RE, Murillo C, Ferro BE, Salas J, Giraldo LE, et al. Polymorphisms in cg2 and pfcrt genes and resistance to chloroquine and other antimalarials in vitro in Plasmodium falciparum isolates from Colombia. Trans R Soc Trop Med Hyg. 2003;97:318-24.
32. Echeverry DF, Holmgren G, Murillo C, Higuita JC, Björkman A, Gil JP, et al. Polymorphisms in the pfcrt and pfmdr1 genes of Plasmodium falciparum and in vitro susceptibility to amodiaquine and desethylamodiaquine. Am J Trop Med Hyg. 2007;77:1034-8.
33. Vieira PP, Ferreira MU, Alecrim MG, Alecrim WD, da Silva LH, Sihuincha MM, et al. pfcrt polymorphism and the spread of chloroquine resistance in Plasmodium falciparum populations across the Amazon Basin. J Infect Dis. 2004;190:417-24.
34. Wootton JC. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature. 2002;418:320-3.
How to Cite
1.
Maestre A, Carmona-Fonseca J, Maestre A. Alta frecuencia de mutaciones puntuales en pfcrt de Plasmodium falciparum y emergencia de nuevos haplotipos mutantes en Colombia. biomedica [Internet]. 2008 Dec. 1 [cited 2024 May 11];28(4):523-30. Available from: https://revistabiomedica.org/index.php/biomedica/article/view/57
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