Proceedings of the National Academy of Sciences of the United States of America · 2018
Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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Sá Juliana M, Kaslow Sarah R, Krause Michael A, Melendez-Muniz Viviana A, Salzman Rebecca E, Kite Whitney A, Zhang Min, Moraes Barros Roberto R, Mu Jianbing, Han Paul K, Mershon J Patrick, Figan Christine E, Caleon Ramoncito L, Rahman Rifat S, Gibson Tyler J, Amaratunga Chanaki, Nishiguchi Erika P, Breglio Kimberly F, Engels Theresa M, Velmurugan Soundarapandian, Ricklefs Stacy, Straimer Judith, Gnädig Nina F, Deng Bingbing, Liu Anna, Diouf Ababacar, Miura Kazutoyo, Tullo Gregory S, Eastman Richard T, Chakravarty Sumana, James Eric R, Udenze Kenneth, Li Suzanne, Sturdevant Daniel E, Gwadz Robert W, Porcella Stephen F, Long Carole A, Fidock David A, Thomas Marvin L, Fay Michael P, Sim B Kim Lee, Hoffman Stephen L, Adams John H, Fairhurst Rick M, Su Xin-Zhuan, Wellems Thomas E
Аннотация
Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t1/2s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC50 measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62-1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76-39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t1/2 calculations by three different methods yielded mean differences of 0.01 h (95% CI, -3.66 to 3.67), 0.80 h (95% CI, -0.92 to 2.53), and 2.07 h (95% CI, 0.77-3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (-13% difference; 95% CI, -58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.