Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Author(s):Show less -

Mita, Toshihiro ^{[1, 2]} ; Culleton, Richard ^[3] ; Takahashi, Nobuyuki ^[1] ; Nakamura, Masatoshi ^[4] ; Tsukahara, Takahiro ^[1] ; Hunja, Carol W. ^{[3, 5, 6]} ; Win, Zin Zayar ^{[2, 7]} ; Htike, Wah Win ^[8] ; Marma, Aung S. ^[1] ; Dysoley, Lek ^{[1, 9]} ; Ndounga, Mathieu ^[10] ; Dzodzomenyo, Mawuli ^{[1, 11]} ; Akhwale, Willis S. ^{[1, 12]} ; Kobayashi, Jun ^[13] ; Uemura, Haruki ^[14] ; Kaneko, Akira ^{[15, 16]} ; Hombhanje, Francis ^[17] ; Ferreira, Marcelo U. ^[18] ; Bjorkman, Anders ^[15] ; Endo, Hiroyoshi ^[1] ; Ohashi, Jun ^[19]

Affiliation:Show less -

^[1] Tokyo Womens Med Univ, Dept Int Affairs & Trop Med, Tokyo - Japan

^[2] Juntendo Univ, Sch Med, Dept Mol & Cellular Parasitol, Tokyo 113 - Japan

^[3] Nagasaki Univ, Inst Trop Med, Dept Pathol, Malaria Unit, Nagasaki 852 - Japan

^[4] Dokkyo Med Univ, Dept Trop Med & Parasitol, Mibu, Tochigi - Japan

^[5] Strathmore Univ, Ctr Res Therapeut Sci, Nairobi - Kenya

^[6] South Eastern Kenya Univ, Kitui - Kenya

^[7] Univ Tokyo, Grad Sch Med, Dept Biomed Chem, Tokyo - Japan

^[8] Univ Med 1, Dept Microbiol, Yangon - Myanmar

^[9] Natl Ctr Parasitol, Entomol & Malaria Control Programe CNM, Phnom Penh - Cambodia

^[10] Ctr Etud Ressources Vegetales, Lab Pharmacol, Brazzaville - Rep Congo

^[11] Univ Ghana, Sch Publ Hlth, Legon - Ghana

^[12] Univ Washington, Dept Global Hlth, I TECH, Seattle, WA 98195 - USA

^[13] Univ Ryukyus, Sch Hlth Sci, Dept Global Hlth, Nishihara, Okinawa 90301 - Japan

^[14] Nagasaki Univ, Inst Trop Med, Dept Protozool, Nagasaki 852 - Japan

^[15] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm - Sweden

^[16] Osaka City Univ, Grad Sch Med, Dept Parasitol, Osaka 558 - Japan

^[17] Divine Word Univ, Ctr Hlth Res & Diagnost, Madang - Papua N Guinea

^[18] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo - Brazil

^[19] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo 113 - Japan

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 60, n. 6, p. 3340-3347, JUN 2016.
• Web of Science Citations: 10

Abstract

The emergence and spread of artemisinin-resistant Plasmodium falciparum is of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the Pfkelch13 gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced the Pfkelch13 propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on the Pfkelch13 propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline of Pfkelch13 polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, various Pfkelch13 mutations have been selected under artemisin in pressure. (AU)