Highly effective artemisinin-based antimalarial drugs are used worldwide and have contributed to reductions in the malaria burden in many areas. Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and its potential spread threatens to reverse recent gains against malaria and to abort plans for a renewed global eradication campaign. Ongoing efforts to contain artemisinin-resistant malaria are hampered by the lack of tools to gauge the extent and direction of its spread. Presently, only laborious clinical trials can reliably measure resistance. A molecular assay to detect markers of artemisinin resistance would be a highly valuable surveillance tool, but the genetic basis of resistance is unknown. We propose genome-wide association studies (GWAS) that aim to identify molecular markers that can be used to track and contain artemisinin-resistant parasites before they spread globally. The work will be accomplished in two aims. First, we will use a dense panel of single nucleotide polymorphisms (SNPs) to map regions of the P. falciparum genome that are associated with artemisinin resistance. To accomplish this, we will use an established SNP- calling pipeline to determine genotypes at ~421,000 SNPs from short-read sequencing data in parasites collected during completed trials of artemisinin efficacy, and we will estimate the association between parasite genotypes and the amount of time it takes to reduce parasitemia by half following artemisinin treatment (i.e. parasite clearance half-life). Associations will be estimated in two independent sample sets, and meta-analysis will be performed to validate genomic regions associated with artemisinin resistance. In the second aim, we will identify and prioritize candidate genes within genomic regions identified in Aim 1 and use next-generation sequencing data to identify polymorphisms within high-priority genes and their association with parasite clearance half-life. If successful, this project will result in the development of a rapid assay to detect candidate markers of artemisinin resistance in subsequent candidate gene association studies, as well as data to begin the functional characterization of candidate genes to better understand the mechanisms underlying resistance.

Public Health Relevance

The most important class of drugs for malaria, the artemisinins, is threatened by the recent emergence of artemisinin-resistant malaria parasites. Since most malaria-endemic countries use artemisinins to treat malaria, the spread of artemisinin-resistant parasites could result in th inability to successfully treat this devastating disease. This project aims to identify parasite genes underlying artemisinin resistance, in an effort to develop tools to track resistant parasites and contain them before they spread globally.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101713-02
Application #
8626355
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Joy, Deirdre A
Project Start
2013-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$409,286
Indirect Cost
$129,785
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
MalariaGEN Plasmodium falciparum Community Project (2016) Genomic epidemiology of artemisinin resistant malaria. Elife 5:
Artimovich, Elena; Schneider, Kristan; Taylor, Terrie E et al. (2015) Persistence of Sulfadoxine-Pyrimethamine Resistance Despite Reduction of Drug Pressure in Malawi. J Infect Dis 212:694-701
Takala-Harrison, Shannon; Jacob, Christopher G; Arze, Cesar et al. (2015) Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis 211:670-9
Huang, Fang; Takala-Harrison, Shannon; Jacob, Christopher G et al. (2015) A Single Mutation in K13 Predominates in Southern China and Is Associated With Delayed Clearance of Plasmodium falciparum Following Artemisinin Treatment. J Infect Dis 212:1629-35
Ouattara, Amed; Kone, Aminatou; Adams, Matthew et al. (2015) Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali. Am J Trop Med Hyg 92:1202-6
Travassos, Mark A; Coulibaly, Drissa; Bailey, Jason A et al. (2015) Differential recognition of terminal extracellular Plasmodium falciparum VAR2CSA domains by sera from multigravid, malaria-exposed Malian women. Am J Trop Med Hyg 92:1190-4
Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A et al. (2015) Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet 47:226-34
Artimovich, Elena; Kapito-Tembo, Atupele; Pensulo, Paul et al. (2015) The effect of local variation in malaria transmission on the prevalence of sulfadoxine-pyrimethamine resistant haplotypes and selective sweep characteristics in Malawi. Malar J 14:387
Takala-Harrison, Shannon; Laufer, Miriam K (2015) Antimalarial drug resistance in Africa: key lessons for the future. Ann N Y Acad Sci 1342:62-7
Brown, Tyler S; Jacob, Christopher G; Silva, Joana C et al. (2015) Plasmodium falciparum field isolates from areas of repeated emergence of drug resistant malaria show no evidence of hypermutator phenotype. Infect Genet Evol 30:318-22

Showing the most recent 10 out of 13 publications