Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1.

Autor: Amambua-Ngwa A; MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia., Button-Simons KA; 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., Brenneman KV; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Ferrari M; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Checkley LA; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Haile MT; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA., Shoue DA; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., McDew-White M; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Tindall SM; School of Life Sciences, University of Nottingham, Nottingham, UK., Reyes A; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Delgado E; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA., Dalhoff H; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Larbalestier JK; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA., Amato R; Wellcome Sanger Institute, Hinxton, UK., Pearson RD; Wellcome Sanger Institute, Hinxton, UK., Taylor AB; Department of Biochemistry & Structural Biology, University of Texas Health Science Center at San Antonio, Antonio, TX, USA., Nosten FH; Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Mae Sot, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., D'Alessandro U; MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia., Kwiatkowski D; Wellcome Sanger Institute, Hinxton, UK., Cheeseman IH; Host Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, USA., 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.; Department of Global Health, University of Washington, Seattle, WA, USA., Avery SV; School of Life Sciences, University of Nottingham, Nottingham, UK., Conway DJ; Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK., Vaughan AM; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA. Ashley.Vaughan@seattlechildrens.org.; Department of Pediatrics, University of Washington, Seattle, WA, USA. Ashley.Vaughan@seattlechildrens.org., Ferdig MT; Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA. ferdig.1@nd.edu., Anderson TJC; Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, USA. tanderso@txbiomed.org.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2023 Jul; Vol. 8 (7), pp. 1213-1226. Date of Electronic Publication: 2023 May 11.
DOI: 10.1038/s41564-023-01377-z
Abstrakt: Malaria parasites break down host haemoglobin into peptides and amino acids in the digestive vacuole for export to the parasite cytoplasm for growth: interrupting this process is central to the mode of action of several antimalarial drugs. Mutations in the chloroquine (CQ) resistance transporter, pfcrt, located in the digestive vacuole membrane, confer CQ resistance in Plasmodium falciparum, and typically also affect parasite fitness. However, the role of other parasite loci in the evolution of CQ resistance is unclear. Here we use a combination of population genomics, genetic crosses and gene editing to demonstrate that a second vacuolar transporter plays a key role in both resistance and compensatory evolution. Longitudinal genomic analyses of the Gambian parasites revealed temporal signatures of selection on a putative amino acid transporter (pfaat1) variant S258L, which increased from 0% to 97% in frequency between 1984 and 2014 in parallel with the pfcrt1 K76T variant. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containing pfaat1 that is selected by CQ treatment. Gene editing demonstrated that pfaat1 S258L potentiates CQ resistance but at a cost of reduced fitness, while pfaat1 F313S, a common southeast Asian polymorphism, reduces CQ resistance while restoring fitness. Our analyses reveal hidden complexity in CQ resistance evolution, suggesting that pfaat1 may underlie regional differences in the dynamics of resistance evolution, and modulate parasite resistance or fitness by manipulating the balance between both amino acid and drug transport.
(© 2023. The Author(s).)
Databáze: MEDLINE
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