Genetic Variation and Evolution of Artemisinin Resistance Malaria is one of the biggest killers in the world. The 2010 World Malaria Report estimates that almost 225 million people each year become acutely ill from the disease-and approximately one million will die from malaria. In the absence of an effective malaria vaccine, chemotherapy remains the mainstay for treatment and prevention of the disease. Genetic variability of the most dangerous type of malaria, Plasmodium falciparum, underlies its transmission success and impedes efforts to control disease. Drug resistance to antimalarial drugs such as antifolates and chloroquine has spread from Asia throughout Africa and resistance to second and third line drugs is now commonplace. Using the tools of population genetics and genomics, the Genetic Variation and Evolution of Artemisinin Resistance project will expand our fundamental understanding of both the genetic variation of malaria and microbial drug resistance among malaria parasites by confirming artemisinin resistance phenotypes, identify the gene (or genes) involved in artemisinin drug resistance, and validate the candidate gene (or genes) involved in artemisinin resistance. Because the emergence of drug resistance threatens to outpace the development of effective new antimalarial drugs, the development of an early warning system for emerging resistance is an essential component to defeating malaria.

Public Health Relevance

Genetic Variation and Evolution of Artemisinin Resistance Chemotherapy remains the mainstay for treatment and prevention of malaria, with current efforts focused on the use of artemisinin-based antimalarial drugs in combination with other partner compounds. New reports of emerging drug resistance signal a threat to the effectiveness of these artemisinin-based drugs. Leveraging genetic variation and evolution, we will identify genetic variants associated with changing artemisinin responses and detect the early stages of drug resistance before catastrophic loss of these still effective anti- malarial compounds takes hold.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099105-03
Application #
8822805
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Joy, Deirdre A
Project Start
2013-04-05
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
Mukherjee, Angana; Gagnon, Dominic; Wirth, Dyann F et al. (2018) Inactivation of Plasmepsins 2 and 3 Sensitizes Plasmodium falciparum to the Antimalarial Drug Piperaquine. Antimicrob Agents Chemother 62:
Cowell, Annie N; Istvan, Eva S; Lukens, Amanda K et al. (2018) Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science 359:191-199
Wong, Wesley; Wenger, Edward A; Hartl, Daniel L et al. (2018) Modeling the genetic relatedness of Plasmodium falciparum parasites following meiotic recombination and cotransmission. PLoS Comput Biol 14:e1005923
Bei, Amy K; Niang, Makhtar; Deme, Awa B et al. (2018) Dramatic Changes in Malaria Population Genetic Complexity in Dielmo and Ndiop, Senegal, Revealed Using Genomic Surveillance. J Infect Dis 217:622-627
Ndiaye, Yaye Dié; Diédhiou, Cyrille K; Bei, Amy K et al. (2017) High resolution melting: a useful field-deployable method to measure dhfr and dhps drug resistance in both highly and lowly endemic Plasmodium populations. Malar J 16:153
Mukherjee, Angana; Bopp, Selina; Magistrado, Pamela et al. (2017) Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia. Malar J 16:195
Wong, Wesley; Griggs, Allison D; Daniels, Rachel F et al. (2017) Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thiès, Senegal. Genome Med 9:5
Rice, Benjamin L; Golden, Christopher D; Anjaranirina, Evelin Jean Gasta et al. (2016) Genetic evidence that the Makira region in northeastern Madagascar is a hotspot of malaria transmission. Malar J 15:596
Molina-Cruz, Alvaro; Zilversmit, Martine M; Neafsey, Daniel E et al. (2016) Mosquito Vectors and the Globalization of Plasmodium falciparum Malaria. Annu Rev Genet 50:447-465
Magistrado, Pamela A; Corey, Victoria C; Lukens, Amanda K et al. (2016) Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL), a Resistance Mechanism for Two Distinct Compound Classes. ACS Infect Dis 2:816-826

Showing the most recent 10 out of 26 publications