Integrative Genetic Manipulation of <i>Plasmodium cynomolgi</i> Reveals Multidrug Resistance-1 Y976F Associated With Increased In Vitro Susceptibility to Mefloquine-Reference-Cited by-同舟云学术

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

Published:2022-12-07 Issue: Volume: Page:
ISSN:0022-1899
Container-title:The Journal of Infectious Diseases
language:en
Short-container-title:

Author:

Ward Kurt E¹²,Christensen Peter²,Racklyeft Annie²,Dhingra Satish K¹,Chua Adeline C Y²³,Remmert Caroline²,Suwanarusk Rossarin²⁴,Matheson Jessica²,Blackman Michael J⁵⁶,Kaneko Osamu⁴,Kyle Dennis E⁷,Lee Marcus C S⁸,Moon Robert W⁶,Snounou Georges⁹,Rénia Laurent³¹⁰¹¹,Fidock David A¹¹²,Russell Bruce²⁴^ORCID,Bifani Pablo³⁶¹³

Affiliation:

1. Department of Microbiology and Immunology, Columbia University Irving Medical Center , New York, New York , USA

2. Department of Microbiology and Immunology, University of Otago , Dunedin , New Zealand

3. A*STAR Infectious Diseases Laboratory, Agency for Science, Technology, and Research , Singapore , Singapore

4. Department of Protozoology, Institute of Tropical Medicine, Nagasaki University , Nagasaki , Japan

5. Malaria Biochemistry Laboratory, Francis Crick Institute , London , United Kingdom

6. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine , London , United Kingdom

7. Center for Tropical and Emerging Global Diseases, University of Georgia , Athens, Georgia , USA

8. Parasites and Microbes Programme, Wellcome Sanger Institute , Hinxton , United Kingdom

9. 11-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Institut de biologie François Jacob, Direction de Recherche Fondamentale, Commissariat à l'énergie atomique et aux énergies alternatives-Université Paris Sud , Fontenay-aux-Roses , France

10. Lee Kong Chian School of Medicine, Nanyang Technological University , Singapore , Singapore

11. School of Biological Sciences, Nanyang Technological University , Singapore , Singapore

12. Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center , New York, New York , USA

13. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore , Singapore

Abstract

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.

Funder

Agency for Science, Technology, and Research, Singapore

Health Research Council

University of Otago

Japanese Society for the Promotion of Science

National Institutes of Health

Agence Nationale de la Recherche

Francis Crick Institute

Cancer Research UK

UK Medical Research Council

Wellcome

MRC