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

Autor: Mok S; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Yeo T; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA., Hong D; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Shears MJ; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Ross LS; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Ward KE; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA., Dhingra SK; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Kanai M; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA., Bridgford JL; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA., Tripathi AK; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Mlambo G; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Burkhard AY; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Ansbro MR; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA., Fairhurst KJ; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA., Gil-Iturbe E; Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA., Park H; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Rozenberg FD; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Kim J; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA., Mancia F; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA., Fairhurst RM; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA., Quick M; Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA., Uhlemann AC; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Sinnis P; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Fidock DA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Nov 10; Vol. 9 (45), pp. eadi2364. Date of Electronic Publication: 2023 Nov 08.
DOI: 10.1126/sciadv.adi2364
Abstrakt: 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.
Databáze: MEDLINE