Multidrug-resistant (MDR) Plasmodium falciparum is partially responsible for the global resurgence of malaria. With the failing of many antimalarial drugs, most malaria-endemic countries have changed to artemisinin-based combination therapies (ACTs). Although ACT is highly effective, recent detection of reduced sensitivity in P. falciparum to artemisinins in several regions of Southeast Asia has raised great concerns. Although eariy resistance detection is essential for deterring and containing resistance, current detecfion of artemisinin resistance relies exclusively on clinical observations and in vitro drug assays. The lack of understanding of the exact mode of action and the mechanism of resistance for artemisinins makes resistance surveillance in areas of artemisinin deployment very difficult. To address this urgent problem, we have selected Thailand, China's Yunnan and Myanmar as our strategic sites to investigate artemisinin resistance. Southeast Asia has been the epicenter of drug resistant malaria parasites. The prevalence of MDR parasites, extensive deployment of artemisinins often as monotherapy, and the detection of reduced susceptibility to artemisinins among parasite populations suggest that artemisinin resistance is likely to arise in this region. In this study, we propose to 1) systematically sample P. falciparum clinical isolates and accurately determine their in vitro sensitivity to a panel of antimalarial drugs including artemisinins;2) determine the correlations of artemisinin-resistance with polymorphisms in the genome using both candidate gene and genome-wide association study (GWAS) approaches;3) validate promising mutations within candidate genes through allelic exchange experiments;and 4) develop molecular methods for detecting the mutation(s) responsible for artemisinin resistance and perform field surveillance of the resistance marker(s). The integrafion of a comprehensive sampling scheme, accurate in vitro drug assays and GWAS will provide essential information for elucidafing the mechanism of artemisinin resistance, understanding how artemisinin resistance evolves, and facilitating the design of molecular methods to closely monitor resistance development in areas of ACT deployment.

Public Health Relevance

Artemisinin is currently our last line of defense against multi-drug resistant malaria parasites. Here we propose to determine the potential mechanism of artemisinin resistance in malaria parasites through systematic sampling of clinical samples in Southeast Asian regions where artemisinin resistance is likely to emerge, in vitro drug assays, and molecular association studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-AWA-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
University Park
United States
Zip Code
Wang, Meilian; Siddiqui, Faiza Amber; Fan, Qi et al. (2016) Limited genetic diversity in the PvK12 Kelch protein in Plasmodium vivax isolates from Southeast Asia. Malar J 15:537
Liu, Huaie; Feng, Guohua; Zeng, Weilin et al. (2016) A more appropriate white blood cell count for estimating malaria parasite density in Plasmodium vivax patients in northeastern Myanmar. Acta Trop 156:152-6
Zhu, Xiaotong; Zhao, Zhenjun; Feng, Yonghui et al. (2016) Genetic diversity of the Plasmodium falciparum apical membrane antigen I gene in parasite population from the China-Myanmar border area. Infect Genet Evol 39:155-62
Wang, Qinghui; Zhao, Zhenjun; Zhang, Xuexing et al. (2016) Naturally Acquired Antibody Responses to Plasmodium vivax and Plasmodium falciparum Merozoite Surface Protein 1 (MSP1) C-Terminal 19 kDa Domains in an Area of Unstable Malaria Transmission in Southeast Asia. PLoS One 11:e0151900
Wang, Xiaoming; Zhou, Guofa; Zhong, Daibin et al. (2016) Life-table studies revealed significant effects of deforestation on the development and survivorship of Anopheles minimus larvae. Parasit Vectors 9:323
Ménard, Didier; Khim, Nimol; Beghain, Johann et al. (2016) A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms. N Engl J Med 374:2453-64
Hu, Yue; Zhou, Guofa; Ruan, Yonghua et al. (2016) Seasonal dynamics and microgeographical spatial heterogeneity of malaria along the China-Myanmar border. Acta Trop 157:12-9
Guo, Suqin; Zhang, Wei; He, Lishan et al. (2016) Rapid evaluation of artesunate quality with a specific monoclonal antibody-based lateral flow dipstick. Anal Bioanal Chem 408:6003-8
Xu, Xin; Zhou, Guofa; Wang, Ying et al. (2016) Microgeographic Heterogeneity of Border Malaria During Elimination Phase, Yunnan Province, China, 2011-2013. Emerg Infect Dis 22:1363-70
Guo, Suqin; He, Lishan; Tisch, Daniel J et al. (2016) Pilot testing of dipsticks as point-of-care assays for rapid diagnosis of poor-quality artemisinin drugs in endemic settings. Trop Med Health 44:15

Showing the most recent 10 out of 88 publications