Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility.

Autor:	Demas AR; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Sharma AI; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Wong W; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Early AM; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142., Redmond S; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142., Bopp S; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Neafsey DE; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142., Volkman SK; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142.; School of Nursing and Health Sciences, Simmons College, Boston, MA 02115., Hartl DL; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; dhartl@oeb.harvard.edu dfwirth@hsph.harvard.edu.; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138., Wirth DF; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; dhartl@oeb.harvard.edu dfwirth@hsph.harvard.edu.; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Dec 11; Vol. 115 (50), pp. 12799-12804. Date of Electronic Publication: 2018 Nov 12.
DOI:	10.1073/pnas.1812317115
Abstrakt:	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 Pf Kelch13 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 Pf Coronin, 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 Pf Kelch13 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 non kelch13 type of resistance to ART in natural settings. Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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