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.

Loading

Article metrics loading...

/content/journals/10.4269/ajtmh.17-0351
2017-11-08
2018-11-17
Loading full text...

Full text loading...

/deliver/fulltext/14761645/97/5/tpmd170351.html?itemId=/content/journals/10.4269/ajtmh.17-0351&mimeType=html&fmt=ahah

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]
  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]
  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]
  4. Tumwebaze P, 2016. Changing antimalarial drug resistance patterns identified by surveillance at three sites in Uganda. J Infect Dis 215: 631635.
  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]
  6. Djimde A, 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257263.[Crossref]
  7. Duraisingh MT, Cowman AF, , 2005. Contribution of the pfmdr1 gene to antimalarial drug-resistance. Acta Trop 94: 181190.[Crossref]
  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]
  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]
  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]
  11. Gregson A, Plowe CV, , 2005. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57: 117145.[Crossref]
  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]
  13. Rosenthal PJ, , 2013. The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 89: 10251038.[Crossref]
  14. Andersson DI, Hughes D, , 2010. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 8: 260271.
  15. Wargo AR, Kurath G, , 2012. Viral fitness: definitions, measurement, and current insights. Curr Opin Virol 2: 538545.[Crossref]
  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]
  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]
  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]
  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]
  20. Rosario VE, Hall R, Walliker D, Beale GH, , 1978. Persistence of drug-resistant malaria parasites. Lancet 1: 185187.[Crossref]
  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]
  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]
  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.
  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]
  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]
  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]
  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]
  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]
  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]
  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]
  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.
  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.
  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]
  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]
  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]
  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]
  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]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.17-0351
Loading
/content/journals/10.4269/ajtmh.17-0351
Loading

Data & Media loading...

Supplementary Data

Supplemental Table

  • Received : 03 May 2017
  • Accepted : 31 May 2017

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