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

Amambua-Ngwa, AORCID logo; Button-Simons, KAORCID logo; Li, XORCID logo; Kumar, SORCID logo; Brenneman, KVORCID logo; Ferrari, M; Checkley, LA; Haile, MTORCID logo; Shoue, DA; McDew-White, M; +18 more...Tindall, SM; Reyes, A; Delgado, EORCID logo; Dalhoff, H; Larbalestier, JKORCID logo; Amato, R; Pearson, RDORCID logo; Taylor, ABORCID logo; Nosten, FHORCID logo; D'Alessandro, UORCID logo; Kwiatkowski, DORCID logo; Cheeseman, IHORCID logo; Kappe, SHORCID logo; Avery, SVORCID logo; Conway, DJORCID logo; Vaughan, AMORCID logo; Ferdig, MTORCID logo; Anderson, TJORCID logo and (2023) Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nature microbiology, 8 (7). pp. 1213-1226. ISSN 2058-5276 DOI: 10.1038/s41564-023-01377-z
Copy

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.


picture_as_pdf
Ngwa-etal-2023-Chloroquine-resistance-evolution-in-plasmodium.pdf
subject
Published Version
Available under Creative Commons: Attribution 4.0

View Download

Atom BibTeX OpenURL ContextObject in Span Multiline CSV OpenURL ContextObject Dublin Core Dublin Core MPEG-21 DIDL Data Cite XML EndNote HTML Citation JSON MARC (ASCII) MARC (ISO 2709) METS MODS RDF+N3 RDF+N-Triples RDF+XML RIOXX2 XML Reference Manager Refer Simple Metadata ASCII Citation EP3 XML
Export

Downloads