Identification of the drug/metabolite transporter 1 as a marker of quinine resistance in a NF54×Cam3.II P. falciparum genetic cross.

Autor:	Kanai M; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Mok S; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, USA., Yeo T; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Shears MJ; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, MD, USA., Ross LS; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA., Jeon JH; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Narwal S; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Haile MT; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA., Tripathi AK; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, MD, USA., Mlambo G; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, MD, USA., Kim J; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, NY, USA., Gil-Iturbe E; Department of Psychiatry, Columbia University Irving Medical Center, NY, USA., Okombo J; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Fairhurst KJ; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Bloxham T; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Bridgford JL; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Sheth T; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Ward KE; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA., Park H; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, USA., Rozenberg FD; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, USA., Quick M; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, NY, USA.; Department of Psychiatry, Columbia University Irving Medical Center, NY, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, NY, USA., Mancia F; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, NY, USA., Lee MCS; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.; Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, UK., Small-Saunders JL; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, USA., Uhlemann AC; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, USA., Sinnis P; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, MD, USA., Fidock DA; Department of Microbiology & Immunology, Columbia University Irving Medical Center, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, NY, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 01. Date of Electronic Publication: 2024 Oct 01.
DOI:	10.1101/2024.09.27.615529
Abstrakt:	The genetic basis of Plasmodium falciparum resistance to quinine (QN), a drug used to treat severe malaria, has long been enigmatic. To gain further insight, we used FRG-NOD human liver-chimeric mice to conduct a P. falciparum genetic cross between QN-sensitive and QN-resistant parasites, which also differ in their susceptibility to chloroquine (CQ). By applying different selective conditions to progeny pools prior to cloning, we recovered 120 unique recombinant progeny. These progeny were subjected to drug profiling and QTL analyses with QN, CQ, and monodesethyl-CQ (md-CQ, the active metabolite of CQ), which revealed predominant peaks on chromosomes 7 and 12, consistent with a multifactorial mechanism of resistance. A shared chromosome 12 region mapped to resistance to all three antimalarials and was preferentially co-inherited with pfcrt . We identified an ATP-dependent zinc metalloprotease (FtsH1) as one of the top candidates and observed using CRISPR/Cas9 SNP-edited lines that ftsh1 is a potential mediator of QN resistance and a modulator of md-CQ resistance. As expected, CQ and md-CQ resistance mapped to a chromosome 7 region harboring pfcrt . However, for QN, high-grade resistance mapped to a chromosome 7 peak centered 295kb downstream of pfcrt . We identified the drug/metabolite transporter 1 (DMT1) as the top candidate due to its structural similarity to PfCRT and proximity to the peak. Deleting DMT1 in QN-resistant Cam3.II parasites significantly sensitized the parasite to QN but not to the other drugs tested, suggesting that DMT1 mediates QN response specifically. We localized DMT1 to structures associated with vesicular trafficking, as well as the parasitophorous vacuolar membrane, lipid bodies, and the digestive vacuole. We also observed that mutant DMT1 transports more QN than the wild-type isoform in vitro . Our study demonstrates that DMT1 is a novel marker of QN resistance and a new chromosome 12 locus associates with CQ and QN response, with ftsh1 is a potential candidate, suggesting these genes should be genotyped in surveillance and clinical settings.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu