A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
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Citations
Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism.
Identification of large variation in pfcrt, pfmdr-1 and pfubp-1 markers in Plasmodium falciparum isolates from Ethiopia and Tanzania.
Investigation and Evaluation of Genetic Diversity of Plasmodium falciparum Kelch 13 Polymorphisms Imported From Southeast Asia and Africa in Southern China
Chloroquine Remains Effective for Treating Plasmodium vivax Malaria in Pursat Province, Western Cambodia
No polymorphisms in K13-propeller gene associated with artemisinin resistance in Plasmodium falciparum isolated from Brazzaville, Republic of Congo
References
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Artemisinin Resistance in Plasmodium falciparum Malaria
Evidence of Artemisinin-Resistant Malaria in Western Cambodia
Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress
Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study
Related Papers (5)
Artemisinin Resistance in Plasmodium falciparum Malaria
Spread of Artemisinin Resistance in Plasmodium falciparum Malaria
K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates
Novel phenotypic assays for the detection of artemisinin- resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies
Frequently Asked Questions (9)
Q2. What future works have the authors mentioned in the paper "A molecular marker of artemisinin-resistant plasmodium falciparum malaria" ?
Further studies are therefore required to identify additional genetic determinants of ART resistance, which may reside in the strongly selected regions recently identified14,16.
Q3. How many mutations are sufficient to confer resistance to ART in a typical African parasite?
it is particularlyworrying that as few as two mutations, that is, the K13-propeller M476I and PF3D7_0110400D56V,were sufficient to conferART resistance toF32Tanzania, which has a typical African genetic background.
Q4. What is the significance of the mutations in the K13propeller?
14 as being under recent positive selection, and within the region of top-ranked signatures of selection outlined in ref. 16; (4) multiple mutations, all non-synonymous, are present in the K13propeller, reflecting positive selection rather than a hitchhiking effect or genetic drift; (5)mutations occur in a domain that is highly conserved inP. falciparum, with only onenon-synonymous SNPbeingdocumented in a single parasite isolate from Africa42; (6) all polymorphisms the authors observe in Cambodia are novel and all but one (V568G) occur at positions strictly conserved between Plasmodium species (Supplementary Fig. 1 and Supplementary Fig. 2), suggesting strong structural and functional constraints on the protein; (7) the three most-prevalent K13-propeller mutations correlate strongly with RSA0–3h survival rates in vitro and parasite clearance half-lives in vivo at the level of individual parasite isolates andmalaria patients, respectively; and (8) the frequency of mutant alleles correlates strongly with the prevalence of day 3 positivity after ACT treatment at the level of human populations in Cambodia.
Q5. What is the definition of aK13-propeller polymorphism?
K13-propeller polymorphism fulfils the definition of a molecularmarker of ART resistance for several reasons: (1) there has been a progressive loss of wild-type parasites in western Cambodia during the decade of emerging ART resistance in this region; (2) mutant parasites cluster in Cambodian provinces where ART resistance is well established and are less prevalent where ART resistance is uncommon; (3) PF3D7_1343700 is located 5.9 kilobases upstreamof the 35-kb locus identified in ref.
Q6. How many SNPs are found in PF3D7?
PF3D7_1464500 has 12 SNPs previously reported in older isolates from southeast Asia, including theART-susceptibleDd2 line21, probably reflecting a geographic signature.
Q7. What is the significance of the ART resistance in a wild type parasite?
Allele exchange studies in mutant and wild-type parasites may help to define the contribution of K13-propeller polymorphisms on different genetic backgrounds to theRSA0–3 h survival rate.
Q8. Who obtained the ethical clearances for P. falciparum isolates?
Ethical clearances for parasite isolate collections were obtained from the CambodianNational Ethics Committee for Health Research, the Institutional Review Board of the Naval Medical Research Center, the Technical Review Group of the WHO Regional Office for the Western Pacific, and the Institutional Review Board of the National Institute of Allergy and Infectious Diseases.
Q9. What is the possible explanation for the ART resistance in Cambodia?
One possible explanation is that the parasite clearance half-life is not only determined by the intrinsic susceptibility of a parasite isolate to ART, but also by its developmental stage at the time of ART treatment and host-related parameters such as pharmacokinetics and immunity17.