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A major genome region underlying artemisinin resistance in malaria

ABSTRACT: Evolving resistance to artemisinin-based compounds in SE Asia threatens to derail attempts to control and eliminate malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) from the blood following treatment. We used a two-phase approach to identify the genes underlying this ongoing selective event. Comparison of geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from western Cambodia, western Thailand and Laos identified 33 strongly selected genome regions. We screened SNPs and microsatellites within these genome regions in 718 parasites from western Thailand, and identified a 35kb region of chr 13 showing strong association (P=10-6 to 10-11) with slow CR. This region contains several compelling candidate loci, such as HSP70, for assessment by transfection. These results illustrate the efficacy of targeted association for identifying the genetic basis of adaptive traits.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE33002 | GEO | 2012/05/01

SECONDARY ACCESSION(S): PRJNA147999

REPOSITORIES: GEO

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Project description:Plasmodium falciparum, the most pathogenic human malaria parasite, infects millions of human beings and causes a serious public health threat. Currently, the most potent anti-malarial drugs are artemisinin and its derivatives1,2. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge3. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources4. Once activated, artemisinins are converted into highly reactive carbon-centered radicals5,6 that attack macromolecules through alkylation and propagate a series of damages, eventually leading to parasite death7,8. Even though several parasite proteins have been reported as the targets of artemisinin9,10, the exact mechanism of artemisinin action is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted. Here, we have developed an unbiased chemical proteomics approach to directly probe the mechanism of action of artemisinin in P. falciparum in situ. An alkyne-tagged artemisinin analogue coupled with biotin enables selective purification and identification of 124 artemisinin covalent-binding protein targets, many of which are involved in essential biological processes of the parasite. In vitro assays confirm the specific artemisinin binding and inhibition of selected targets. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using the alkyne-tagged artemisinin coupled with a fluorescent dye to monitor its protein binding, we showed that heme, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The extremely high level of heme released from the hemoglobin digestion by the parasite make artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages) compared to parasites at early ring stage, which have low level of heme, mainly from endogenous synthesis. The ‘blood eating’ nature of the parasite with the release of large amounts of heme confers artemisinin with extremely high specificity against the parasites, with minimum side effects towards healthy red blood cells. Taken together, our results established a unifying model to explain the action and specificity of artemisinin in parasite killing. Our findings could facilitate the development of better alternative strategies to treat malaria in times of emerging artemisinin resistance11,12.

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A major genome region underlying artemisinin resistance in malaria

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