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Fitness costs of antimalarial drug resistance

English title Fitness costs of antimalarial drug resistance
Applicant Felger Ingrid
Number 112196
Funding scheme Project funding (Div. I-III)
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Tropical Medicine
Start/End 01.05.2006 - 28.02.2010
Approved amount 296'000.00
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All Disciplines (3)

Discipline
Tropical Medicine
Medical Statistics
Molecular Biology

Keywords (6)

malria; plasmodium falciparum drug resistance; molecular epidemiology; fitness costs; evolution and modeling of drug resistance; SNP genotyping

Lay Summary (English)

Lead
Lay summary
Drug targets are molecules that are essential for a pathogen’s physiology.
Drugs against the malaria parasite Plasmodium falciparum target metabolic enzymes or transmembrane transporters. Point mutations in those parasite genes were found to be associated with drug resistance. In a haploid organism, such as P. falciparum, mutations affecting metabolic and transport processes are expected to be exposed to strong natural selection. Mutations deviating from the evolutionary optimal biochemical structure are likely to be disadvantageous in the absence of drug, and natural selection acts against the changes induced by mutation. Thus, fitness of a mutant parasite is reduced relative to the non-mutated parasite. This reduction is termed ‘fitness costs of drug resistance’.
Defining the costs of antimalarial drug resistance will provide a variable that is urgently needed for modelling the evolution and spread of drug resistance. Such models are currently developed and increasingly applied to direct public health measures and policy making.

The costs incurred by mutations are difficult to measure in vivo because fitness, measured as increase or decrease in offspring numbers, eludes direct experimental quantification in a natural parasite population due to technical and ethical obstacles. To estimate transmission success to new hosts, a few surrogate markers have been used, such as asexual parasite densities or gametocyte counts. Our approach is to estimate the probability of transmission via a model that describes the relationship between asexual parasite densities of P. falciparum and the infectivity to mosquitoes. For each genotype the relative transmission probability will be predicted. The selection coefficient as a measure of the extent to which natural selection reduces the relative contribution of a genotype to the next generation is derived directly from transmission probabilities.

This first attempt ever to measure fitness costs of drug resistance mutations directly in the human host in a malaria endemic area comprises detection by microarray technology of 36 single point mutations in 5 genes associated with malaria drug resistance. The duration of infection of individual parasite clones is determined by genotyping consecutive blood samples from 300 children from Papua New Guinea followed over 16 months.Fitness of mutant versus wild type parasite clones is determined by estimating the transmission probability using asexual density and survival of individual clones in the host.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Estimating the numbers of malaria infections in blood samples using high-resolution genotyping data
Ross Amanda, Koepfli Cristian, Xiaohong Li, Schoepflin Sonja, Siba Peter, Mueller Ivo, Felger Ingrid, Smith Thomas (2012), Estimating the numbers of malaria infections in blood samples using high-resolution genotyping data, in PLoS ONE, 7(8), e42496.
Multiplicity and diversity of Plasmodium vivax infections in a highly endemic region in Papua New Guinea
Koepfli Cristian, Ross Amanda, Kiniboro Benson, Smith Thomas A, Zimmerman Peter, Siba Peter, Mueller Ivo, Felger Ingrid (2011), Multiplicity and diversity of Plasmodium vivax infections in a highly endemic region in Papua New Guinea, in PLoS Neglected Tropical Diseases, 5(12), e1424.
How much remains undetected? Probability of molecular detection of human Plasmodia in the field
Koepfli Cristian, Schoepflin Sonja, Bretscher Michael, Lin Enmoore, Kiniboro Benson, Zimmerman Peter, Siba Peter, Smith Thomas A, Mueller Ivo, Felger Ingrid (2011), How much remains undetected? Probability of molecular detection of human Plasmodia in the field, in PLoS ONE, 6(4), e19010.
Treatment with coartem (artemether-lumefantrine) in Papua New Guinea
Schoepflin Sonja, Lin Enmoore, Kiniboro Benson, DaRe Jeana, Mehlotra Rajeev, Zimmerman Peter, Mueller Ivo, Felger Ingrid (2010), Treatment with coartem (artemether-lumefantrine) in Papua New Guinea, in The American journal of tropical medicine and hygiene, 82(4), 529-534.
Differential patterns of infection and disease with P. falciparum and P. vivax in young Papua New Guinean children
Lin Enmoore, Kiniboro Benson, Gray Laurie, Dobbie Stuart, Robinson Leanne, Laumaea Annemarie, Schopflin Sonja, Stanisic Danielle, Betuela Inoni, Blood-Zikursh Melinda, Siba Peter, Felger Ingrid, Schofield Louis, Zimmerman Peter, Mueller Ivo (2010), Differential patterns of infection and disease with P. falciparum and P. vivax in young Papua New Guinean children, in PLoS ONE, 5(2), e9047.
Comparison of Plasmodium falciparum allelic frequency distribution in different endemic settings by high-resolution genotyping
Schoepflin Sonja, Valsangiacomo Francesca, Lin Enmoore, Kiniboro Benson, Mueller Ivo, Felger Ingrid (2009), Comparison of Plasmodium falciparum allelic frequency distribution in different endemic settings by high-resolution genotyping, in Malaria Journal, 8, 250.
Evaluation of Plasmodium vivax genotyping markers for molecular monitoring in clinical trials
Koepfli Cristian, Mueller Ivo, Marfurt Jutta, Goroti Mary, Sie Albert, Oa Olive, Genton Blaise, Beck Hans-Peter, Felger Ingrid (2009), Evaluation of Plasmodium vivax genotyping markers for molecular monitoring in clinical trials, in The Journal of infectious diseases, (199), 1074-1080.
Fitness costs of resistance to antimalarial drugs
Felger Ingrid, Beck Hans-Peter (2008), Fitness costs of resistance to antimalarial drugs, in Trends in Parasitology, 24(8), 331-333.
Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population
Schoepflin Sonja, Marfurt Jutta, Goroti Mary, Baisor Moses, Mueller Ivo, Felger Ingrid (2008), Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population, in Malaria Journal, 7, 78.

Collaboration

Group / person Country
Types of collaboration
Case Western Reserve University, Cleveland United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Papua New Guinea Institute of Medical Research PapuaNew Guinea (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
134889 Molecular tools for monitoring the impact of intensified malaria control on malaria epidemiology 01.04.2011 Project funding (Div. I-III)
125316 Estimating transition rates for epidemiological models of endemic Plasmodium vivax malaria 01.04.2009 Project funding (Div. I-III)
159580 Epidemiology of ultra-low density malaria infections and their relevance for control and elimination 01.05.2015 Project funding (Div. I-III)

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