Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model

Sa Juliana M.; Kaslow Sarah R.; Krause Michael A.Melendez-Muniz Viviana A.Salzman Rebecca E.Kite Whitney A.Zhang MinBarros Roberto R. MoraesMu JianbingHan Paul K.Mershon J. PatrickFigan Christine E.Caleon Ramoncito L.Rahman Rifat S.Gibson Tyler J.Amaratunga ChanakiNishiguchi Erika P.Breglio Kimberly F.Engels Theresa M.Velmurugan SoundarapandianRicklefs StacyStraimer JudithGnadig Nina F.Deng BingbingLiu AnnaDiouf AbabacarMiura KazutoyoTullo Gregory S.Eastman Richard T.Chakravarty SumanaJames Eric R.Udenze KennethLi SuzanneSturdevant Daniel E.Gwadz Robert W.Porcella Stephen F.Long Carole A.Fidock David A.Thomas Marvin L.Fay Michael P.Sim B. Kim LeeHoffman Stephen L.Adams John H.Fairhurst Rick M.Su Xin-zhuanWellems Thomas E.

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Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model

机译：Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model

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Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t(1/2)s ( 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, t(1/2) 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 (76H10(C580Rev)) 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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第49期|12513-12518|共6页
作者
Sa Juliana M.; Kaslow Sarah R.; Krause Michael A.Melendez-Muniz Viviana A.Salzman Rebecca E.Kite Whitney A.Zhang MinBarros Roberto R. MoraesMu JianbingHan Paul K.Mershon J. PatrickFigan Christine E.Caleon Ramoncito L.Rahman Rifat S.Gibson Tyler J.Amaratunga ChanakiNishiguchi Erika P.Breglio Kimberly F.Engels Theresa M.Velmurugan SoundarapandianRicklefs StacyStraimer JudithGnadig Nina F.Deng BingbingLiu AnnaDiouf AbabacarMiura KazutoyoTullo Gregory S.Eastman Richard T.Chakravarty SumanaJames Eric R.Udenze KennethLi SuzanneSturdevant Daniel E.Gwadz Robert W.Porcella Stephen F.Long Carole A.Fidock David A.Thomas Marvin L.Fay Michael P.Sim B. Kim LeeHoffman Stephen L.Adams John H.Fairhurst Rick M.Su Xin-zhuanWellems Thomas E.;
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作者单位

Univ S Florida, Coll Publ Hlth, Ctr Global Hlth & Infect Dis Res, Tampa, FL 33612 USA;

NIAID, Res Technol Branch, NIH, Hamilton, MT 59840 USA;

NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USASanaria, Rockville, MD 20850 USAColumbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USANIH, Div Vet Res, Off Res Serv, Bldg 10, Bethesda, MD 20892 USANIAID, Biostat Res Branch, NIH, Rockville, MD 20852 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
malaria; artemisinin-based combination chemotherapy; recrudescence; parasite clearance time; genetic cross;

Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model

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