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Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility
Allison R Demas1, Aabha I Sharma1, Wesley Wong1
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
Abstract:
Drug resistance is an obstacle to global malaria control, as evidenced by the recent emergence and rapid spread of delayed artemisinin (ART) clearance by mutant forms of the PfKelch13 protein in Southeast Asia. Identifying genetic determinants of ART resistance in African-derived parasites is important for surveillance and for understanding the mechanism of resistance. In this study, we carried out long-term in vitro selection of two recently isolated West African parasites (from Pikine and Thiès, Senegal) with increasing concentrations of dihydroartemisinin (DHA), the biologically active form of ART, over a 4-y period. We isolated two parasite clones, one from each original isolate, that exhibited enhanced survival to DHA in the ring-stage survival assay. Whole-genome sequence analysis identified 10 mutations in seven different genes. We chose to focus on the gene encoding PfCoronin, a member of the WD40-propeller domain protein family, because mutations in this gene occurred in both independent selections, and the protein shares the β-propeller motif with PfKelch13 protein. For functional validation, when pfcoronin mutations were introduced into the parental parasites by CRISPR/Cas9-mediated gene editing, these mutations were sufficient to reduce ART susceptibility in the parental lines. The discovery of a second gene for ART resistance may yield insights into the molecular mechanisms of resistance. It also suggests that pfcoronin mutants could emerge as a nonkelch13 type of resistance to ART in natural settings.
Insights
Drug resistance to artemisinin (ART) is a global malaria threat. Researchers identified mutations in the PfCoronin gene in African parasites, revealing a new mechanism for ART resistance beyond the PfKelch13 gene.
Area of Science:
- Malariology
- Genetics
- Drug Resistance
Background:
- Drug resistance, particularly to artemisinin (ART), poses a significant challenge to global malaria control efforts.
- The emergence of delayed ART clearance due to mutations in the Plasmodium falciparum Kelch13 (PfKelch13) protein in Southeast Asia highlights the urgent need to identify new resistance mechanisms.
- Understanding the genetic basis of ART resistance in African parasite strains is crucial for effective surveillance and developing countermeasures.
Purpose of the Study:
- To identify novel genetic determinants of artemisinin (ART) resistance in African-derived Plasmodium falciparum parasites.
- To investigate the role of the PfCoronin gene in ART resistance, given its structural similarity to PfKelch13 and its involvement in independent drug selections.
- To functionally validate the contribution of PfCoronin mutations to reduced susceptibility to dihydroartemisinin (DHA).
Main Methods:
- Long-term in vitro selection of West African Plasmodium falciparum isolates using increasing concentrations of dihydroartemisinin (DHA) over four years.
- Isolation and characterization of parasite clones exhibiting enhanced survival to DHA in ring-stage survival assays.
- Whole-genome sequencing to identify mutations, followed by CRISPR/Cas9-mediated gene editing to introduce PfCoronin mutations into parental parasites for functional validation.
Main Results:
- Two independent parasite selections resulted in clones with significantly enhanced survival to DHA.
- Whole-genome sequencing identified ten mutations across seven genes, with mutations in the PfCoronin gene occurring in both selections.
- Introduction of PfCoronin mutations into parental parasites via gene editing was sufficient to reduce susceptibility to DHA, confirming its role in ART resistance.
Conclusions:
- The study identifies PfCoronin as a second gene, in addition to PfKelch13, associated with artemisinin (ART) resistance in Plasmodium falciparum.
- Mutations in PfCoronin can confer reduced susceptibility to dihydroartemisinin (DHA), suggesting a novel molecular mechanism for ART resistance.
- PfCoronin mutants represent a potential emerging non-PfKelch13 type of ART resistance that warrants monitoring in natural settings for global malaria control surveillance.
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