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)
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Special Emphasis Panel (ZAI1-AWA-M)
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Pennsylvania State University
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Cui, Liwang; Lindner, Scott; Miao, Jun (2015) Translational regulation during stage transitions in malaria parasites. Ann N Y Acad Sci 1342:9-Jan
Xu, Tielong; Zhong, Daibin; Tang, Linhua et al. (2014) Anopheles sinensis mosquito insecticide resistance: comparison of three mosquito sample collection and preparation methods and mosquito age in resistance measurements. Parasit Vectors 7:54
Yuan, Lili; Hao, Mingming; Wu, Lanou et al. (2014) Refrigeration provides a simple means to synchronize in vitro cultures of Plasmodium falciparum. Exp Parasitol 140:18-23
Putaporntip, Chaturong; Miao, Jun; Kuamsab, Napaporn et al. (2014) The Plasmodium vivax merozoite surface protein 3? sequence reveals contrasting parasite populations in southern and northwestern Thailand. PLoS Negl Trop Dis 8:e3336
Gupta, Bhavna; Xu, Shuhui; Wang, Zenglei et al. (2014) Plasmodium falciparum multidrug resistance protein 1 (pfmrp1) gene and its association with in vitro drug susceptibility of parasite isolates from north-east Myanmar. J Antimicrob Chemother 69:2110-7
Li, Peipei; Zhao, Zhenjun; Wang, Ying et al. (2014) Nested PCR detection of malaria directly using blood filter paper samples from epidemiological surveys. Malar J 13:175
Zhou, Guofa; Sun, Ling; Xia, Rongji et al. (2014) Clinical malaria along the China-Myanmar border, Yunnan Province, China, January 2011-August 2012. Emerg Infect Dis 20:675-8
Qin, Qian; Li, Yiji; Zhong, Daibin et al. (2014) Insecticide resistance of Anopheles sinensis and An. vagus in Hainan Island, a malaria-endemic area of China. Parasit Vectors 7:92
Zhu, Guoding; Zhong, Daibin; Cao, Jun et al. (2014) Transcriptome profiling of pyrethroid resistant and susceptible mosquitoes in the malaria vector, Anopheles sinensis. BMC Genomics 15:448
Wang, Zenglei; Liu, Min; Liang, Xiaoying et al. (2014) A flow cytometry-based quantitative drug sensitivity assay for all Plasmodium falciparum gametocyte stages. PLoS One 9:e93825

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