INCREASING PREVALENCE OF WILDTYPES IN THE DIHYDROFOLATE REDUCTASE GENE OF PLASMODIUM FALCIPARUM IN AN AREA WITH HIGH LEVELS OF SULFADOXINE/PYRIMETHAMINE RESISTANCE AFTER INTRODUCTION OF TREATED BED NETS

MICHAEL ALIFRANGIS Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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MARTHA M. LEMNGE Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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ANITA M. RØNN Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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METHOD D. SEGEJA Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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STEPHEN M. MAGESA Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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INSAF F. KHALIL Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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IB C. BYGBJERG Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; National Institute for Medical Research, Amani Research Centre, Amani, Tanga, Tanzania

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In Magoda and Mpapayu villages in Tanzania, we have previously found comparable high prevalence of Plasmodium falciparum resistance to sulfadoxine/pyrimethamine (S/P) in vivo and of mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes of P. falciparum responsible for resistance to S/P. In December 1998, Magoda received insecticide-treated nets (ITNs), whereas ITNs were introduced in Mpapayu in March 2001. We have studied the effect of ITNs on P. falciparum resistance genes by monitoring the prevalence of dhfr and dhps genotypes in children less than five years old living in the villages from 1998 to 2000. In 2000, after two years of bed net use, the prevalence of wild types in codon 51, 59, and 108 of dhfr increased significantly in Magoda compared with previous years. Furthermore, the prevalence of dhfr wild types was significantly higher in Magoda than in Mpapayu in 2000. The impact of ITNs on the transmission intensity seems not only to affect the overall malaria morbidity, but may even facilitate restoration of susceptibility to antimalarial drugs.

Author Notes

Reprint requests: Michael Alifrangis, Panum Institute, Institue of Medical Microbiology and Immunology, Building 24.2, Blegdamsvej 3, 2200 Copenhagen N, Denmark, Telephone: 45-3532-7676, Fax: 45-3532-7851, E-mail: malif@biobase.dk.
  • 1

    White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK, Danis M, Greenwood BM, Anderson RM, Olliaro P, 1999. Averting a malaria disaster. Lancet 353 :1965–1967.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Hastings IM, D’Alessandro U, 2000. Modelling a predictable disaster: the rise and spread of drug-resistant malaria. Parasitol Today 16 :340–347.

  • 3

    Cowman A, Morry MJ, Biggs BA, Cross GAM, Foote SJ, 1988. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 85 :9109–9113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Snewin VA, England SM, Sims PF, Hyde JE, 1989. Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine. Gene 76 :41–52.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV, 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 94 :1124–1129.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Triglia T, Cowman A, 1994. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 91 :7149–7153.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Brooks DR, Wang P, Read M, Watkins WM, Sims PF, Hyde JE, 1994. Sequence variation of the hydroxymethyldihydropterin pyrophosphokinase: dihydropteroate synthase gene lines of the human malaria parasite, Plasmodium falciparum, with differing resistance to sulfadoxine. Eur J Biochem 224 :397–405.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Omar SA, Adagu IS, Warhurst DC, 2001. Can pretreatment screening for dhps and dhfr point mutations in Plasmodium falciparum infections be used to predict sulfadoxine-pyrimeth-amine treatment failure? Trans R Soc Trop Med Hyg 95 :315–319.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Nzila AM, Nduati E, Mberu EK, Hopkins SC, Monks SA, Winstanley PA, Watkins WM, 2000. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethamine/sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 181 :2023–2028.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Wang P, Lee C-S, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins MW, Sims PFG, Hyde JE, 1997. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol Biochem Parasitol 89 :161–177.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Basco LK, Tahar R, Keundjian A, Ringwald P, 2000. Sequence variations in the genes encoding dihydropteroate synthase and dihydrofolate reductase and clinical response to sulfadoxine-pyrimethamine in patients with acute uncomplicated falciparum malaria. J Infect Dis 182 :624–628.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    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, 2002. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 185 :380–388.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Lengeler C, 2000. Insecticide-treated bednets and curtains for preventing malaria. Cochrane Database Syst Rev CD000363.

    • PubMed
    • Export Citation
  • 14

    Greenwood BM, 1997. What’s new in malaria control? Ann Trop Med Parasitol 91 :523–531.

  • 15

    D’Alessandro U, Olaleye BO, McGuire W, Thomson MC, Langerock P, Bennett S, Greenwood BM, 1995. A comparison of the efficacy of insecticide-treated and untreated bed nets in preventing malaria in Gambian children. Trans R Soc Trop Med Hyg 89 :596–598.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Choi HW, Breman JG, Teutsch SM, Liu S, Hightower AW, Sexton JD, 1995. The effectiveness of insecticide-impregnated bed nets in reducing cases of malaria infection: a meta-analysis of published results. Am J Trop Med Hyg 52 :377–382.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Maxwell CA, Msuya E, Sudi M, Njunwa KJ, Carneiro IA, Curtis CF, 2002. Effect of community-wide use of insecticide-treated nets for 3-4 years on malarial morbidity in Tanzania. Trop Med Int Health 7 :1003–1008.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Molyneux DH, Floyd K, Barnish G, Fevre EM, 1999. Transmission control and drug resistance in malaria: a crucial interaction. Parasitol Today 15 :238–240.

  • 19

    Mackinnon MJ, Hastings IM, 1998. The evolution of multiple drug resistance in malaria parasites. Trans R Soc Trop Med Hyg 92 :188–195.

  • 20

    Lemnge MM, Msangeni HA, Rønn AM, Salum FM, Jakobsen PH, Mhina J, Akida JA, Bygbjerg IC, 1997. Maloprim malaria prophylaxis in children living in a holoendemic village in north-eastern Tanzania. Trans R Soc Trop Med Hyg 91 :68–73.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Rønn AM, Msangeni HA, Mhina J, Wernsdorfer WH, Bygbjerg IC, 1996. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania. Trans R Soc Trop Med Hyg 90 :179–181.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Jelinek T, Rønn AM, Lemnge MM, Curtis J, Mhina J, Duraisingh MT, Bygbjerg IC, Warhurst DC, 1998. Polymorphisms in dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes of Plasmodium falciparum and in vivo resistance to sulfadoxine/pyrimethamine in isolates from Tanzania. Trop Med Int Health 3 :605–609.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Sambrook J, Fritsch EF, Maniatis T, 1989. Molecular Cloning: A Laboratory Manual. Second edition. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.

    • PubMed
    • Export Citation
  • 24

    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.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Duraisingh MT, Curtis J, Warhurst DC, 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp Parasitol 89 :1–8.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Trigg JK, Mbwana H, Chambo O, Hills E, Watkins W, Curtis CF, 1997. Resistance to pyrimethamine/sulfadoxine in Plasmodium falciparum in 12 villages in north east Tanzania and a test of chlorproguanil/dapsone. Acta Trop 63 :185–189.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills E, Watkins W, 2001. Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania. Lancet 358 :1218–1223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Wernsdorfer WH, Payne D, 1991. The dynamics of drug resistance in Plasmodium falciparum. Pharmacol Ther 50 :95–121.

  • 29

    Mackinnon MJ, 1997. Survival probability of drug resistant mutants in malaria parasites. Proc R Soc Lond B Biol Sci 264 :53–59.

  • 30

    Mockenhaupt FP, May J, Eggelte TA, Thies FL, Ademowo OG, Bienzle U, Meyer CG, 1999. Short report: high prevalence and imbalanced age distribution of the Plasmodium falciparum dihydrofolate reductase gene Asn108 mutation in an area of low pyrimethamine usage in Nigeria. Am J Trop Med Hyg 61 :375–377.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Yohannes K, Dulhunty JM, Kourleoutov C, Manuopangai VT, Polyn MK, Parks WJ, Williams GM, Bryan JH, 2000. Malaria control in central Malaita, Solomon Islands. 1. The use of insecticide-impregnated bed nets. Acta Trop 75 :173–183.

    • PubMed
    • Search Google Scholar
    • Export Citation
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