Mapping the genomic landscape of multidrug resistance in <i>Plasmodium falciparum</i> and its impact on parasite fitness-Reference-Cited by-同舟云学术

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Published:2023-11-10 Issue:45 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Mok Sachel¹²³^ORCID,Yeo Tomas¹²^ORCID,Hong Davin¹²⁴^ORCID,Shears Melanie J.⁵^ORCID,Ross Leila S.¹^ORCID,Ward Kurt E.¹²^ORCID,Dhingra Satish K.¹,Kanai Mariko¹²^ORCID,Bridgford Jessica L.¹²^ORCID,Tripathi Abhai K.⁵^ORCID,Mlambo Godfree⁵^ORCID,Burkhard Anna Y.¹,Ansbro Megan R.⁶^ORCID,Fairhurst Kate J.¹²,Gil-Iturbe Eva⁷^ORCID,Park Heekuk³^ORCID,Rozenberg Felix D.³^ORCID,Kim Jonathan⁸^ORCID,Mancia Filippo⁸^ORCID,Fairhurst Rick M.⁶,Quick Matthias⁷⁸⁹^ORCID,Uhlemann Anne-Catrin²³^ORCID,Sinnis Photini⁵^ORCID,Fidock David A.¹²³^ORCID

Affiliation:

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

2. Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.

3. Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

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

5. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

6. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.

7. Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.

8. Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.

9. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.

Abstract

Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adi2364

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