1921
Volume 97, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

Controlling malaria in high transmission areas, such as much of sub-Saharan Africa, will require concerted efforts to slow the spread of drug resistance and to impede malaria transmission. Understanding the fitness costs associated with the development of drug resistance, particularly within the context of transmission, can help guide policy decisions to accomplish these goals, as fitness constraints might lead to decreased transmission of drug-resistant strains. To determine if resistance–mediating polymorphisms impact on development at different parasite stages, we compared the genotypes of parasites infecting humans and mosquitoes from households in Uganda. Genotypes at 14 polymorphic loci in genes encoding putative transporters ( and and folate pathway enzymes ( and were characterized using ligase detection reaction-fluorescent microsphere assays. In paired analysis using the Wilcoxon signed-rank test, prevalences of mutations at 12 loci did not differ significantly between parasites infecting humans and mosquitoes. However, compared with parasites infecting humans, those infecting mosquitoes were enriched for the 86Y mutant allele ( = 0.0001) and those infecting s.s. were enriched for the 86Y ( = 0.0001) and 76T ( = 0.0412) mutant alleles. Our results suggest modest directional selection resulting from varied fitness costs during the life cycle. Better appreciation of the fitness implications of drug resistance mediating mutations can inform optimal malaria treatment and prevention strategies.

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References

  1. Yeka A, 2016. Artesunate/amodiaquine versus artemether/lumefantrine for the treatment of uncomplicated malaria in Uganda: a randomized trial. J Infect Dis 213: 11341142.[Crossref] [Google Scholar]
  2. Yeka A, Dorsey G, Kamya MR, Talisuna A, Lugemwa M, Rwakimari JB, Staedke SG, Rosenthal PJ, Wabwire-Mangen F, Bukirwa H, , 2008. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda. PLoS One 3: e2390.[Crossref] [Google Scholar]
  3. Conrad MD, 2014. Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children. J Infect Dis 210: 344353.[Crossref] [Google Scholar]
  4. Tumwebaze P, 2016. Changing antimalarial drug resistance patterns identified by surveillance at three sites in Uganda. J Infect Dis 215: 631635. [Google Scholar]
  5. Tumwebaze P, 2015. Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from Ugandan children. Antimicrob Agents Chemother 59: 30183030.[Crossref] [Google Scholar]
  6. Djimde A, 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257263.[Crossref] [Google Scholar]
  7. Duraisingh MT, Cowman AF, , 2005. Contribution of the pfmdr1 gene to antimalarial drug-resistance. Acta Trop 94: 181190.[Crossref] [Google Scholar]
  8. Mwai L, Kiara SM, Abdirahman A, Pole L, Rippert A, Diriye A, Bull P, Marsh K, Borrmann S, Nzila A, , 2009. In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother 53: 50695073.[Crossref] [Google Scholar]
  9. Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Bjorkman A, Gil JP, , 2005. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis 191: 10141017.[Crossref] [Google Scholar]
  10. Zongo I, Dorsey G, Rouamba N, Tinto H, Dokomajilar C, Guiguemde RT, Rosenthal PJ, Ouedraogo JB, , 2007. Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial. Lancet 369: 491498.[Crossref] [Google Scholar]
  11. Gregson A, Plowe CV, , 2005. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57: 117145.[Crossref] [Google Scholar]
  12. Arinaitwe E, 2013. Intermittent preventive therapy with sulfadoxine-pyrimethamine for malaria in pregnancy: a cross-sectional study from Tororo, Uganda. PLoS One 8: e73073.[Crossref] [Google Scholar]
  13. Rosenthal PJ, , 2013. The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 89: 10251038.[Crossref] [Google Scholar]
  14. Andersson DI, Hughes D, , 2010. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 8: 260271. [Google Scholar]
  15. Wargo AR, Kurath G, , 2012. Viral fitness: definitions, measurement, and current insights. Curr Opin Virol 2: 538545.[Crossref] [Google Scholar]
  16. Peters JM, Chen N, Gatton M, Korsinczky M, Fowler EV, Manzetti S, Saul A, Cheng Q, , 2002. Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum . Antimicrob Agents Chemother 46: 24352441.[Crossref] [Google Scholar]
  17. Hayward R, Saliba KJ, Kirk K, , 2005. pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum . Mol Microbiol 55: 12851295.[Crossref] [Google Scholar]
  18. Preechapornkul P, Imwong M, Chotivanich K, Pongtavornpinyo W, Dondorp AM, Day NP, White NJ, Pukrittayakamee S, , 2009. Plasmodium falciparum pfmdr1 amplification, mefloquine resistance, and parasite fitness. Antimicrob Agents Chemother 53: 15091515.[Crossref] [Google Scholar]
  19. Ochong E, Tumwebaze PK, Byaruhanga O, Greenhouse B, Rosenthal PJ, , 2013. Fitness consequences of Plasmodium falciparum pfmdr1 polymorphisms inferred from ex vivo culture of Ugandan parasites. Antimicrob Agents Chemother 57: 42454251.[Crossref] [Google Scholar]
  20. Rosario VE, Hall R, Walliker D, Beale GH, , 1978. Persistence of drug-resistant malaria parasites. Lancet 1: 185187.[Crossref] [Google Scholar]
  21. Shinondo CJ, Lanners HN, Lowrie RC, Jr Wiser MF, , 1994. Effect of pyrimethamine resistance on sporogony in a Plasmodium berghei/Anopheles stephensi model. Exp Parasitol 78: 194202.[Crossref] [Google Scholar]
  22. Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, Djimde AA, Kouriba B, Taylor TE, Plowe CV, , 2003. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187: 18701875.[Crossref] [Google Scholar]
  23. Wang X, Mu J, Li G, Chen P, Guo X, Fu L, Chen L, Su X, Wellems TE, , 2005. Decreased prevalence of the Plasmodium falciparum chloroquine resistance transporter 76T marker associated with cessation of chloroquine use against P. falciparum malaria in Hainan, People’s Republic of China. Am J Trop Med Hyg 72: 410414. [Google Scholar]
  24. Ord R, Alexander N, Dunyo S, Hallett R, Jawara M, Targett G, Drakeley CJ, Sutherland CJ, , 2007. Seasonal carriage of pfcrt and pfmdr1 alleles in Gambian Plasmodium falciparum imply reduced fitness of chloroquine-resistant parasites. J Infect Dis 196: 16131619.[Crossref] [Google Scholar]
  25. Mharakurwa S, Kumwenda T, Mkulama MA, Musapa M, Chishimba S, Shiff CJ, Sullivan DJ, Thuma PE, Liu K, Agre P, , 2011. Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes. Proc Natl Acad Sci U S A 108: 1879618801.[Crossref] [Google Scholar]
  26. Mharakurwa S, Sialumano M, Liu K, Scott A, Thuma P, , 2013. Selection for chloroquine-sensitive Plasmodium falciparum by wild Anopheles arabiensis in southern Zambia. Malar J 12: 453.[Crossref] [Google Scholar]
  27. Mendes C, Salgueiro P, Gonzalez V, Berzosa P, Benito A, do Rosario VE, de Sousa B, Cano J, Arez AP, , 2013. Genetic diversity and signatures of selection of drug resistance in Plasmodium populations from both human and mosquito hosts in continental Equatorial Guinea. Malar J 12: 114.[Crossref] [Google Scholar]
  28. Kamya MR, 2015. Malaria transmission, infection, and disease at three sites with varied transmission intensity in Uganda: implications for malaria control. Am J Trop Med Hyg 92: 903912.[Crossref] [Google Scholar]
  29. Kilama M, 2014. Estimating the annual entomological inoculation rate for Plasmodium falciparum transmitted by Anopheles gambiae s.l. using three sampling methods in three sites in Uganda. Malar J 13: 111.[Crossref] [Google Scholar]
  30. Muhindo MK, 2016. Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda. Malar J 15: 437.[Crossref] [Google Scholar]
  31. Gillies MT, Coetzee M, , 1987. A Supplement to the Anophelinae of Africa South of the Sahara. Johannesburg, South Africa: The South African Institute for Medical Research. [Google Scholar]
  32. Gillies MT, DeMeillon B, , 1968. The Anophelinae of Africa South of the Sahara (Ethiopian Zoogeographical Region). Johannesburg, South Africa: The South African Institute for Medical Research. [Google Scholar]
  33. Britton S, Cheng Q, Sutherland CJ, McCarthy JS, , 2015. A simple, high-throughput, colourimetric, field applicable loop-mediated isothermal amplification (HtLAMP) assay for malaria elimination. Malar J 14: 335.[Crossref] [Google Scholar]
  34. Scott JA, Brogdon WG, Collins FH, , 1993. Identification of single specimens of the Anopheles gambiae complex by the polymerase chain reaction. Am J Trop Med Hyg 49: 520529.[Crossref] [Google Scholar]
  35. Plowe CV, Djimde A, Bouare M, Doumbo O, Wellems TE, , 1995. Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. Am J Trop Med Hyg 52: 565568.[Crossref] [Google Scholar]
  36. LeClair NP, Conrad MD, Baliraine FN, Nsanzabana C, Nsobya S, Rosenthal PJ, , 2013. Optimization of a ligase detection reaction-fluorescent microsphere assay for characterization of resistance-mediating polymorphisms in African samples of Plasmodium falciparum . J Clin Microbiol 51: 25642570.[Crossref] [Google Scholar]
  37. Duraisingh MT, Curtis J, Warhurst DC, , 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase gene by PCR and resitriction digestion. Exp Parasitol 89: 18.[Crossref] [Google Scholar]
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  • Received : 03 May 2017
  • Accepted : 31 May 2017

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