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

Juliana M. Sá, Sarah R. Kaslow, Michael A. Krause, Viviana A. Melendez-Muniz, Rebecca E. Salzman, Whitney A. Kite, Min Zhang, Roberto R. Moraes Barros, Jianbing Mu, Paul K. Han, J. Patrick Mershon, Christine E. Figan, Ramoncito L. Caleon, Rifat S. Rahman, Tyler J. Gibson, Chanaki Amaratunga, Erika P. Nishiguchi, Kimberly F. Breglio, Theresa M. Engels, Soundarapandian VelmuruganStacy Ricklefs, Judith Straimer, Nina F. Gnädig, Bingbing Deng, Anna Liu, Ababacar Diouf, Kazutoyo Miura, Gregory S. Tullo, Richard T. Eastman, Sumana Chakravarty, Eric R. James, Kenneth Udenze, Suzanne Li, Daniel E. Sturdevant, Robert W. Gwadz, Stephen F. Porcella, Carole A. Long, David A. Fidock, Marvin L. Thomas, Michael P. Fay, B. Kim Lee Sim, Stephen L. Hoffman, John H. Adams, Rick M. Fairhurst, Xin zhuan Su, Thomas E. Wellems

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12513-12518
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number49
DOIs
StatePublished - Dec 4 2018
Externally publishedYes

Keywords

  • Artemisinin-based combination chemotherapy
  • Genetic cross
  • Malaria
  • Parasite clearance time
  • Recrudescence

ASJC Scopus subject areas

  • General

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