Emergence of chloroquine resistance in Cambodian Plasmodium vivax threatens the entire malaria control strategy in the region. In collaboration with the Pasteur Institute in Cambodia, we will collect blood samples from 280 individuals infected with P. vivax and use next generation sequencing to investigate the patterns of genetic diversity across the entire P. vivax genome. First, we will conduct population genomic analyses to characterize the structure of the parasite population and better understand how and how fast drug resistance alleles can spread across the country. We will also use these data to identify loci under positive selection which could be responsible for drug resistance. Second, we will determine drug susceptibility of the P. vivax strains present in 100 vivax malaria patients using a combination of in vivo and ex vivo approaches. We will then conduct a genome-wide association study to identify genetic polymorphisms statistically associated with drug resistance in P. vivax. Our findings will improve our understanding of drug resistance in this neglected human malaria parasite and have the potential to significantly advance vivax malaria control.

Public Health Relevance

Extensive use of antimalarial drugs in the past decades has led to the emergence of resistant Plasmodium vivax parasites which greatly complicates malaria elimination. We will combine modern fieldwork with state-of- the-art genomic analyses to understand how drug resistance can spread in a population and identify the genetic bases of this resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI103228-02
Application #
8660615
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Joy, Deirdre A
Project Start
2013-05-13
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Auburn, Sarah; Serre, David; Pearson, Richard D et al. (2016) Genomic Analysis Reveals a Common Breakpoint in Amplifications of the Plasmodium vivax Multidrug Resistance 1 Locus in Thailand. J Infect Dis 214:1235-42
Friedrich, Lindsey R; Popovici, Jean; Kim, Saorin et al. (2016) Complexity of Infection and Genetic Diversity in Cambodian Plasmodium vivax. PLoS Negl Trop Dis 10:e0004526
Chan, Ernest R; Barnwell, John W; Zimmerman, Peter A et al. (2015) Comparative analysis of field-isolate and monkey-adapted Plasmodium vivax genomes. PLoS Negl Trop Dis 9:e0003566
Popovici, Jean; Kao, Sokheng; Eal, Leanghor et al. (2015) Reduced polymorphism in the Kelch propeller domain in Plasmodium vivax isolates from Cambodia. Antimicrob Agents Chemother 59:730-3
Hester, James; Chan, Ernest R; Menard, Didier et al. (2013) De novo assembly of a field isolate genome reveals novel Plasmodium vivax erythrocyte invasion genes. PLoS Negl Trop Dis 7:e2569