Journal
SCIENCE
Volume 347, Issue 6220, Pages 428-431Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1260867
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Funding
- NIH [R01 AI109023]
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH
- French Agence Nationale de la Recherche [ANR-13-BSV3-0018-01]
- French Agence Nationale de la Recherche (Laboratoire d'Excellence IBEID)
- Institut Pasteur, Division International (ACIP) [A-10-2010]
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV3-0018] Funding Source: Agence Nationale de la Recherche (ANR)
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The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from <= 0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.
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