TY - JOUR
T1 - Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model
AU - Sá, Juliana M.
AU - Kaslow, Sarah R.
AU - Krause, Michael A.
AU - Melendez-Muniz, Viviana A.
AU - Salzman, Rebecca E.
AU - Kite, Whitney A.
AU - Zhang, Min
AU - Moraes Barros, Roberto R.
AU - Mu, Jianbing
AU - Han, Paul K.
AU - Patrick Mershon, J.
AU - Figan, Christine E.
AU - Caleon, Ramoncito L.
AU - Rahman, Rifat S.
AU - Gibson, Tyler J.
AU - Amaratunga, Chanaki
AU - Nishiguchi, Erika P.
AU - Breglio, Kimberly F.
AU - Engels, Theresa M.
AU - Velmurugan, Soundarapandian
AU - Ricklefs, Stacy
AU - Straimer, Judith
AU - Gnädig, Nina F.
AU - Deng, Bingbing
AU - Liu, Anna
AU - Diouf, Ababacar
AU - Miura, Kazutoyo
AU - Tullo, Gregory S.
AU - Eastman, Richard T.
AU - Chakravarty, Sumana
AU - James, Eric R.
AU - Udenze, Kenneth
AU - Li, Suzanne
AU - Sturdevant, Daniel E.
AU - Gwadz, Robert W.
AU - Porcella, Stephen F.
AU - Long, Carole A.
AU - Fidock, David A.
AU - Thomas, Marvin L.
AU - Fay, Michael P.
AU - Kim Lee Sim, B.
AU - Hoffman, Stephen L.
AU - Adams, John H.
AU - Fairhurst, Rick M.
AU - Su, Xin zhuan
AU - Wellems, Thomas E.
N1 - Funding Information:
of Allergy and Infectious Diseases, National Institutes of Health, and partially funded by Grants R01 AI109023 (to D.A.F.), R01 AI094973 (to J.H.A.), and R01 AI117017 (to J.H.A.).
Funding Information:
Mark Billinger, and Eric P. Horton for IT advice; and Jose M. C. Ribeiro, Louis H. Miller, and Sanjay A. Desai for comments on the manuscript. This study was supported by the Intramural Research Program of the National Institute
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/12/4
Y1 - 2018/12/4
N2 - 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 dihydroartemi-sinin 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.
AB - 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 dihydroartemi-sinin 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.
KW - Artemisinin-based combination chemotherapy
KW - Genetic cross
KW - Malaria
KW - Parasite clearance time
KW - Recrudescence
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U2 - 10.1073/pnas.1813386115
DO - 10.1073/pnas.1813386115
M3 - Article
C2 - 30455312
AN - SCOPUS:85057607005
VL - 115
SP - 12513
EP - 12518
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 49
ER -