Charles A Narh1,2, Anita Ghansah1, Michael F Duffy2,3, Shazia Ruybal-Pesántez2, Christiana O Onwona1, Abraham R Oduro4, Kwadwo A Koram1, Karen P Day2,3, Kathryn E Tiedje2,3. 1. Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana. 2. School of BioSciences, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, Melbourne, Australia. 3. Department of Microbiology and Immunology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute and Peter Doherty Institute, Melbourne, Australia. 4. Navrongo Health Research Centre, Ghana Health Service, Navrongo, Ghana.
Abstract
BACKGROUND: The majority of Plasmodium falciparum infections, constituting the reservoir in all ages, are asymptomatic in high-transmission settings in Africa. The role of this reservoir in the evolution and spread of drug resistance was explored. METHODS: Population genetic analyses of the key drug resistance-mediating polymorphisms were analyzed in a cross-sectional survey of asymptomatic P. falciparum infections across all ages in Bongo District, Ghana. RESULTS: Seven years after the policy change to artemisinin-based combination therapies in 2005, the pfcrt K76 and pfmdr1 N86 wild-type alleles have nearly reached fixation and have expanded via soft selective sweeps on multiple genetic backgrounds. By constructing the pfcrt-pfmdr1-pfdhfr-pfdhps multilocus haplotypes, we found that the alleles at these loci were in linkage equilibrium and that multidrug-resistant parasites have not expanded in this reservoir. For pfk13, 32 nonsynonymous mutations were identified; however, none were associated with artemisinin-based combination therapy resistance. CONCLUSIONS: The prevalence and selection of alleles/haplotypes by antimalarials were similar to that observed among clinical cases in Ghana, indicating that they do not represent 2 subpopulations with respect to these markers. Thus, the P. falciparum reservoir in all ages can contribute to the maintenance and spread of antimalarial resistance.
BACKGROUND: The majority of Plasmodium falciparum infections, constituting the reservoir in all ages, are asymptomatic in high-transmission settings in Africa. The role of this reservoir in the evolution and spread of drug resistance was explored. METHODS: Population genetic analyses of the key drug resistance-mediating polymorphisms were analyzed in a cross-sectional survey of asymptomatic P. falciparum infections across all ages in Bongo District, Ghana. RESULTS: Seven years after the policy change to artemisinin-based combination therapies in 2005, the pfcrt K76 and pfmdr1 N86 wild-type alleles have nearly reached fixation and have expanded via soft selective sweeps on multiple genetic backgrounds. By constructing the pfcrt-pfmdr1-pfdhfr-pfdhps multilocus haplotypes, we found that the alleles at these loci were in linkage equilibrium and that multidrug-resistant parasites have not expanded in this reservoir. For pfk13, 32 nonsynonymous mutations were identified; however, none were associated with artemisinin-based combination therapy resistance. CONCLUSIONS: The prevalence and selection of alleles/haplotypes by antimalarials were similar to that observed among clinical cases in Ghana, indicating that they do not represent 2 subpopulations with respect to these markers. Thus, the P. falciparum reservoir in all ages can contribute to the maintenance and spread of antimalarial resistance.
Authors: Harald Noedl; Youry Se; Kurt Schaecher; Bryan L Smith; Duong Socheat; Mark M Fukuda Journal: N Engl J Med Date: 2008-12-08 Impact factor: 91.245
Authors: Patrick Tumwebaze; Stephen Tukwasibwe; Aimee Taylor; Melissa Conrad; Emmanuel Ruhamyankaka; Victor Asua; Andrew Walakira; Joaniter Nankabirwa; Adoke Yeka; Sarah G Staedke; Bryan Greenhouse; Samuel L Nsobya; Moses R Kamya; Grant Dorsey; Philip J Rosenthal Journal: J Infect Dis Date: 2017-02-15 Impact factor: 5.226
Authors: T J Anderson; B Haubold; J T Williams; J G Estrada-Franco; L Richardson; R Mollinedo; M Bockarie; J Mokili; S Mharakurwa; N French; J Whitworth; I D Velez; A H Brockman; F Nosten; M U Ferreira; K P Day Journal: Mol Biol Evol Date: 2000-10 Impact factor: 16.240
Authors: Ricardo Ataide; Elizabeth A Ashley; Rosanna Powell; Jo-Anne Chan; Michael J Malloy; Katherine O'Flaherty; Eizo Takashima; Christine Langer; Takafumi Tsuboi; Arjen M Dondorp; Nicholas P Day; Mehul Dhorda; Rick M Fairhurst; Pharath Lim; Chanaki Amaratunga; Sasithon Pukrittayakamee; Tran Tinh Hien; Ye Htut; Mayfong Mayxay; M Abul Faiz; James G Beeson; Francois Nosten; Julie A Simpson; Nicholas J White; Freya J I Fowkes Journal: Proc Natl Acad Sci U S A Date: 2017-03-13 Impact factor: 11.205
Authors: Colin J Sutherland; Ali Alloueche; Jill Curtis; Chris J Drakeley; Rosalynn Ord; Manoj Duraisingh; Brian M Greenwood; Margaret Pinder; David Warhurst; Geoffrey A T Targett Journal: Am J Trop Med Hyg Date: 2002-12 Impact factor: 2.345
Authors: Miriam K Laufer; Shannon Takala-Harrison; Fraction K Dzinjalamala; O Colin Stine; Terrie E Taylor; Christopher V Plowe Journal: J Infect Dis Date: 2010-09-01 Impact factor: 5.226