A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance.

التفاصيل البيبلوغرافية
العنوان: A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance.
المؤلفون: Kane J; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Li X; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Kumar S; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA., Button-Simons KA; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Brenneman KMV; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Dahlhoff H; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Sievert MAC; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Checkley LA; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Shoue DA; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Singh PP; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Abatiyow BA; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA., Haile MT; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA., Nair S; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Reyes A; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Tripura R; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford Old Road Campus, Oxford, UK., Peto T; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford Old Road Campus, Oxford, UK., Lek D; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.; School of Public Health, National Institute of Public Health, Phnom Penh, Cambodia., Kappe SHI; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA., Dhorda M; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford Old Road Campus, Oxford, UK., Nkhoma SC; BEI Resources, American Type Culture Collection (ATCC), Manassas, VA, USA., Cheeseman IH; Host Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Vaughan AM; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA., Anderson TJC; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Ferdig MT; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 17. Date of Electronic Publication: 2023 Sep 17.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: Piperaquine (PPQ) is widely used in combination with dihydroartemisinin (DHA) as a first-line treatment against malaria parasites. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the Plasmodium falciparum chloroquine resistance transporter ( pfcrt ) and increased copies of plasmepsin II/III ( pm2/3 ). We generated a cross between a Cambodia-derived multi-drug resistant KEL1/PLA1 lineage isolate (KH004) and a drug susceptible parasite isolated in Malawi (Mal31). Mal31 harbors a wild-type (3D7-like ) pfcrt allele and a single copy of pm2/3, while KH004 has a chloroquine-resistant (Dd2-like ) pfcrt allele with an additional G367C substitution and four copies of pm2/3 . We recovered 104 unique recombinant progeny and examined a targeted set of progeny representing all possible combinations of variants at pfcrt and pm2/3 for detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes, including PPQ survival assay (PSA), area under the dose-response curve (AUC), and a limited point IC 50 (LP-IC 50 ). We find that inheritance of the KH004 pfcrt allele is required for PPQ resistance, whereas copy number variation in pm2/3 further enhances resistance but does not confer resistance in the absence of PPQ-R-associated mutations in pfcrt . Deeper investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions of pfcrt, pm2/3, and parasite genetic background, to a range of PPQ-related traits and confirm the critical role of the PfCRT G367C substitution in PPQ resistance.
التعليقات: Update in: mBio. 2024 Jul 17;15(7):e0080524. doi: 10.1128/mbio.00805-24. (PMID: 38912775)
معلومات مُعتمدة: C06 RR013556 United States RR NCRR NIH HHS; R37 AI048071 United States AI NIAID NIH HHS; P01 AI127338 United States AI NIAID NIH HHS; P51 OD011133 United States OD NIH HHS; United Kingdom WT_ Wellcome Trust
تواريخ الأحداث: Date Created: 20230925 Latest Revision: 20240717
رمز التحديث: 20240717
مُعرف محوري في PubMed: PMC10515748
DOI: 10.1101/2023.06.06.543862
PMID: 37745488
قاعدة البيانات: MEDLINE
الوصف
تدمد:2692-8205
DOI:10.1101/2023.06.06.543862