- Open Access
Questions over high frequency of mutant PfATP6 haplotypes in traveller isolates
© Woodrow et al.; license Biomed Central Ltd. 2012
Received: 17 May 2012
Accepted: 1 June 2012
Published: 8 June 2012
A recent paper in Malaria Journal suggests that a high proportion of Plasmodium falciparum isolates found in travellers returning from a range of African countries carry the PfATP6 A623E S769N haplotype, and that this genotype is associated with artemether resistance. Such a finding would represent a substantial departure from the extensive literature reporting these individual mutations to be very rare, with the double mutation never documented. The number of isolates screened to obtain these double mutants is unstated, but highly relevant, not least because selection of isolates could have introduced significant confounders, such as timing of in vitro testing. An additional concern relates to the location of sequencing primers used to assess these positions. In the absence of clear information on these fundamental questions it would be appropriate to treat the findings with caution.
Previous publications on prevalence of the A623E and S769N polymorphisms in the countries described by Pillai et al.
The finding of A623E S769N double mutants in 11 of 28 patients in one centre is, therefore, highly unexpected. The authors propose that natural selection for these polymorphisms may be taking place in the countries of origin for these parasites, because of the rapid scale up of anti-malarial treatment programmes being implemented in recent years. However, before natural selection is invoked, a much more basic concern needs to be addressed, namely selection of isolates in the laboratory. It is notable that the median date of receipt for the mutant isolates was around 500 days before that of the wild-type samples (according to the supplementary data). This is of profound methodological importance since use of wild-type controls with different properties to the mutant population (such as date of assay) would introduce a significant confounder. How many isolates were screened to obtain the final 11 double mutants? And how were the wild-type controls selected?
In the absence of clear information on these fundamental questions it would be appropriate to treat the findings and conclusions of the article with caution.
- Pillai DR, Lau R, Khairnar K, Lepore R, Via A, Staines HM, Krishna S: Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections. Malar J. 2012, 11: 131-10.1186/1475-2875-11-131.PubMed CentralView ArticlePubMedGoogle Scholar
- Mugittu K, Genton B, Mshinda H, Beck HP: Molecular monitoring of Plasmodium falciparum resistance to artemisinin in Tanzania. Malar J. 2006, 5: 126-10.1186/1475-2875-5-126.PubMed CentralView ArticlePubMedGoogle Scholar
- Menegon M, Sannella AR, Majori G, Severini C: Detection of novel point mutations in the Plasmodium falciparum ATPase6 candidate gene for resistance to artemisinins. Parasitol Int. 2008, 57: 233-235. 10.1016/j.parint.2007.12.004.View ArticlePubMedGoogle Scholar
- Dahlstrom S, Veiga MI, Ferreira P, Martensson A, Kaneko A, Andersson B, Bjorkman A, Gil JP: Diversity of the sarco/endoplasmic reticulum Ca(2+)-ATPase orthologue of Plasmodium falciparum (PfATP6). Infect Genet Evol. 2008, 8: 340-345. 10.1016/j.meegid.2008.02.002.View ArticlePubMedGoogle Scholar
- Tahar R, Ringwald P, Basco LK: Molecular epidemiology of malaria in Cameroon. XXVIII. In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum and sequence analysis of the P. falciparum ATPase 6 gene. Am J Trop Med Hyg. 2009, 81: 13-18.PubMedGoogle Scholar
- Menegon M, Pearce RJ, Inojosa WO, Pisani V, Abel PM, Matondo A, Bisoffi Z, Majori G, Ord R, Warhurst DC, Roper C, Severini C: Monitoring for multidrug-resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola. Trop Med Int Health. 2009, 14: 1251-1257. 10.1111/j.1365-3156.2009.02369.x.View ArticlePubMedGoogle Scholar
- Tanabe K, Zakeri S, Palacpac NM, Afsharpad M, Randrianarivelojosia M, Kaneko A, Marma AS, Horii T, Mita T: Spontaneous mutations in the Plasmodium falciparum sarcoplasmic/endoplasmic reticulum Ca2 + −ATPase (PfATP6) gene among geographically widespread parasite populations unexposed to artemisinin-based combination therapies. Antimicrob Agents Chemother. 2011, 55: 94-100. 10.1128/AAC.01156-10.PubMed CentralView ArticlePubMedGoogle Scholar
- Menemedengue V, Sahnouni K, Basco L, Tahar R: Molecular epidemiology of malaria in Cameroon. XXX. sequence analysis of Plasmodium falciparum ATPase 6, dihydrofolate reductase, and dihydropteroate synthase resistance markers in clinical isolates from children treated with an artesunate-sulfadoxine-pyrimethamine combination. Am J Trop Med Hyg. 2011, 85: 22-25. 10.4269/ajtmh.2011.10-0523.PubMed CentralView ArticlePubMedGoogle Scholar
- Kwansa-Bentum B, Ayi I, Suzuki T, Otchere J, Kumagai T, Anyan WK, Osei JH, Asahi H, Ofori MF, Akao N, Wilson MD, Boakye DA, Ohta N: Plasmodium falciparum isolates from southern Ghana exhibit polymorphisms in the SERCA-type PfATPase6 though sensitive to artesunate in vitro. Malar J. 2011, 10: 187-10.1186/1475-2875-10-187.PubMed CentralView ArticlePubMedGoogle Scholar
- Kamugisha E, Jing S, Minde M, Kataraihya J, Kongola G, Kironde F, Swedberg G: Efficacy of artemether-lumefantrine in treatment of malaria among under-fives and prevalence of drug resistance markers in Igombe-Mwanza, north-western Tanzania. Malar J. 2012, 11: 58-10.1186/1475-2875-11-58.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.