Integrative Genetic Manipulation of Plasmodium cynomolgi Reveals Multidrug Resistance-1 Y976F Associated With Increased In Vitro Susceptibility to Mefloquine

Kurt E. Ward, Peter Christensen, Annie Racklyeft, Satish K. Dhingra, Adeline C. Y. Chua, Caroline Remmert, Rossarin Suwanarusk, Jessica Matheson, Michael J. Blackman, Osamu Kaneko, Dennis E. Kyle, Marcus C. S. Lee, Robert W. Moon, Georges Snounou, Laurent Rénia, David A. Fidock, Bruce Russell (Lead / Corresponding author), Pablo Bifani

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
27 Downloads (Pure)

Abstract

The lack of a long-term in vitro culture method has severely restricted the study of Plasmodium vivax, in part because it limits genetic manipulation and reverse genetics. We used the recently optimized Plasmodium cynomolgi Berok in vitro culture model to investigate the putative P. vivax drug resistance marker MDR1 Y976F. Introduction of this mutation using clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9) increased sensitivity to mefloquine, but had no significant effect on sensitivity to chloroquine, amodiaquine, piperaquine, and artesunate. To our knowledge, this is the first reported use of CRISPR-Cas9 in P. cynomolgi, and the first reported integrative genetic manipulation of this species.

Original languageEnglish
Pages (from-to)1121-1126
Number of pages6
JournalThe Journal of infectious diseases
Volume227
Issue number10
Early online date7 Dec 2022
DOIs
Publication statusPublished - 15 May 2023

Keywords

  • Plasmodium cynomolgi
  • Plasmodium vivax
  • antimalarial drug resistance
  • chloroquine
  • CRISPR-Cas9
  • mefloquine
  • molecular markers

ASJC Scopus subject areas

  • General Medicine

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