In recent years, there has been an increased appreciation that global malaria elimination efforts cannot succeed without a better understanding of Plasmodium vivax, the most prevalent malaria species outside Africa. In particular, our poor understanding of P. vivax's ability to establish dormant hypnozoite stages that reactivate to cause periodic relapse is a major barrier to malaria elimination due to the lack of deployable anti-relapse therapy. This proposal will use new genomic technologies to achieve a better understanding of the genetic determinants of vivax relapse, with the ultimate goal of identifying targets for therapeutic intervention. Specifically, in light of limited experimental models of vivax, we will apply next generation sequencing techniques to clinical samples from vivax-infected Cambodian patients to provide the first detailed look at the genetic signatures of relapsing parasites.
In Aim 1, we will use amplicon deep sequencing to characterize the in-host diversity of initial and recurrent vivax infections in this cohort. Results will be combined with microsatellite genotyping, population genetic analysis, and statistical modeling to distinguish relapses from re-infections and identify genetic variants predisposed to relapse. We will then whole genome sequence parasites causing relapsing vs. non-relapsing infection in Aim 2 to search for genetic polymorphisms associated with relapse. Our overall hypothesis is that frequently relapsing parasites contain polymorphisms in sporozoite (pre-hypnozoite) specific genes that increase hypnozoite formation and confer increased relapse potential. The candidate is an Assistant Professor in the Division of Infectious Diseases at the University of North Carolina. She has field experience in Southeast Asia, and has pursued clinical and molecular epidemiologic research in malaria for the past 5 years at UNC's Gillings School of Global Public Health. The proposed investigations will build on this foundation to equip her with new skills in genomics, bioinformatics, population genetics, and genetic epidemiology essential for conducting malaria genomics research. She will draw on her mentors'pioneering efforts in next generation sequencing of malaria as well as their respective expertise in malaria epidemiology, population genomics, and the application of these disciplines to public health. The Award will also provide protected time for her to attend didactic courses and hands-on workshops, and to finish a Master's of Science in Clinical Research that includes training in clinical study design. Combined with the preliminary data and tools developed via her research, this training will allow her to pursue R01 funding to conduct genome wide association studies of relapse using large vivax cohorts. The candidate's long-term goal is to become a leading vivax clinical scientist who combines sophisticated molecular tools with clinical studies to help achieve elimination of malaria. Her mentors and her division have a long track record in nurturing successful physician-scientists. They are committed to helping her achieve independence as a translational investigator devoted to understanding the genetic basis of vivax relapse.

Public Health Relevance

Plasmodium vivax is the leading cause of malaria outside Africa. Its propensity for relapse has hindered global efforts to eliminate malaria. This work will improve our ability to identify relapsing parasites and establish tools for uncovering the genetic basis of relapse to inform the design of better anti-relapse drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI110651-01
Application #
8679282
Study Section
Microbiology and Infectious Diseases Research Committee (MID)
Program Officer
Joy, Deirdre A
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Parobek, Christian M; Parr, Jonathan B; Brazeau, Nicholas F et al. (2017) Partner-Drug Resistance and Population Substructuring of Artemisinin-Resistant Plasmodium falciparum in Cambodia. Genome Biol Evol 9:1673-1686
Chaorattanakawee, Suwanna; Lon, Chanthap; Chann, Soklyda et al. (2017) Measuring ex vivo drug susceptibility in Plasmodium vivax isolates from Cambodia. Malar J 16:392
Lin, Jessica T; Meshnick, Steven R; Saunders, David L et al. (2016) Reply to Goncalves et al. J Infect Dis 213:1517
Bassat, Quique; Velarde, Mar; Mueller, Ivo et al. (2016) Key Knowledge Gaps for Plasmodium vivax Control and Elimination. Am J Trop Med Hyg 95:62-71
Parobek, Christian M; Lin, Jessica T; Saunders, David L et al. (2016) Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia. Proc Natl Acad Sci U S A 113:E8096-E8105
Lin, Jessica T; Ubalee, Ratawan; Lon, Chanthap et al. (2016) Microscopic Plasmodium falciparum Gametocytemia and Infectivity to Mosquitoes in Cambodia. J Infect Dis 213:1491-4
Brazeau, Nicholas F; Hathaway, Nicholas; Parobek, Christian M et al. (2016) Longitudinal Pooled Deep Sequencing of the Plasmodium vivax K12 Kelch Gene in Cambodia Reveals a Lack of Selection by Artemisinin. Am J Trop Med Hyg 95:1409-1412
Lin, Jessica T; Hathaway, Nicholas J; Saunders, David L et al. (2015) Using Amplicon Deep Sequencing to Detect Genetic Signatures of Plasmodium vivax Relapse. J Infect Dis 212:999-1008
Chaorattanakawee, Suwanna; Saunders, David L; Sea, Darapiseth et al. (2015) Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance. Antimicrob Agents Chemother 59:4631-43
Chaorattanakawee, Suwanna; Lanteri, Charlotte A; Sundrakes, Siratchana et al. (2015) Attenuation of Plasmodium falciparum in vitro drug resistance phenotype following culture adaptation compared to fresh clinical isolates in Cambodia. Malar J 14:486

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