Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

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Abstract

We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination.

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Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

Aung Pyae Phyo, Aung Phyo, Standwell Nkhoma … (2012)

Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.

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Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum.

T. J. Anderson, B Haubold, J T Williams … (2000)

Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in diversity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific samples (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of diversity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.

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Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Magnus Manske, Olivo Miotto, Susana Campino … (2012)

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. 1,2 Here we describe methods for large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short term culture. Analysis of 86,158 exonic SNPs that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

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Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 22 July 2013

Publication date (Electronic): 28 April 2013

Publication date (Print): June 2013

Publication date PMC-release: 28 October 2013

Volume: 45

Issue: 6

Electronic Location Identifier: 10.1038/ng.2624

Affiliations

[1 ]MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, UK

[2 ]Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok 10400, Thailand

[3 ]Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

[4 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK

[5 ]National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

[6 ]National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia

[7 ]Department of Immunology and Medicine, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand

[8 ]US Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Phnom Penh, Cambodia

[9 ]Armed Forces Health Surveillance Center, Silver Spring MD 20904, USA

[10 ]Navrongo Health Research Centre, Navrongo, Ghana

[11 ]Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand

[12 ]Howard Hughes Medical Institute, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

[13 ]Shoklo Malaria Research Unit, Mae Sot, Tak 63110, Thailand

[14 ]Centre for Tropical Medicine, University of Oxford, Oxford OX3 7LJ, UK

[15 ]Global Malaria Programme, World Health Organization, Geneva, Switzerland

[16 ]Unité d’Immunologie Moléculaire des Parasites, Institut Pasteur, Paris 75015, France

[17 ]Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam

[18 ]MRC Laboratories, Fajara, The Gambia

[19 ]London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK

[20 ]Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali

[21 ]Institut de Recherche en Sciences de la Santé, Direction Régionale de l’Ouést, Bobo-Dioulasso, Burkina Faso

[22 ]Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territories 0811, Australia

[23 ]Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK

[24 ]Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK

Author notes

[* ]Correspondence and requests for materials should be addressed to dominic@ 123456sanger.ac.uk

Author Contributions SC, CA, PL, SuS, SrS, JMA, SD, CN, CMC, DS, YS, CL, MMF, LA-E, AVOH, VA, MI, FN, X-ZS, PR, FA, CD, TTH, MFB, CQT, AA-N, DJC, AD, OKD, IZ, J-BO, SA, NPD, NJW, DB, AMD, CVP and RMF carried out field and laboratory studies to obtain P. falciparum samples for sequencing. CA, PL, SS, JMA, SD, CN, CMC, DS, YS, CL, MMF, FN, X-ZS, PR, FA, NJW, DB, AMD, CVP and RMF carried out clinical studies to obtain ART phenotype data. SC, DA, ED, MS, SA, OK, SO, BM, CIN and MB developed and implemented methods for sample processing and sequencing library preparation. OM, JA-G, MM, GM, VRR, DJ and AM developed software for data management and visualisation. KAR, CH, DA and MM carried out validation experiments. CVP, ST-H, GMV and RMF contributed to development of the project. BM, MB, CIN and JCR provided project management and oversight. OM, JA-G, MM, JO’B, CG and CS carried out data analyses. DPK, OM and JA-G wrote the manuscript. All Authors reviewed the manuscript.

Article

Manuscript ID: EMS53146

DOI: 10.1038/ng.2624

PMC ID: 3807790

PubMed ID: 23624527

SO-VID: 233d2578-0292-428b-9dc4-6f35e7d642f2

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Funding

Funded by: Wellcome Trust :

Award ID: 090770 || WT

Funded by: Wellcome Trust :

Award ID: 082370 || WT

Funded by: Medical Research Council :

Award ID: G19/9 || MRC_

Funded by: Medical Research Council :

Award ID: G0600718 || MRC_

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Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

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Most cited references 39

Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum.

Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

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