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

Ward, Kurt E; Christensen, Peter; Racklyeft, Annie; Dhingra, Satish K; Chua, Adeline CY; Remmert, Caroline; Suwanarusk, Rossarin; Matheson, Jessica; Blackman, Michael J; Kaneko, Osamu; +8 more... Kyle, Dennis E; Lee, Marcus CS; Moon, Robert W; Snounou, Georges; Rénia, Laurent; Fidock, David A; Russell, Bruce; Bifani, Pablo; (2023) Integrative Genetic Manipulation of Plasmodium cynomolgi Reveals Multidrug Resistance-1 Y976F Associated With Increased In Vitro Susceptibility to Mefloquine. The Journal of infectious diseases, 227 (10). pp. 1121-1126. ISSN 0022-1899 DOI: https://doi.org/10.1093/infdis/jiac469

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.

Additional Information

Item Type	Article
Faculty and Department	Faculty of Infectious and Tropical Diseases > Department of Infection Biology
PubMed ID	36478252
Elements ID	197255
Official URL	http://dx.doi.org/10.1093/infdis/jiac469