An amino acid transporter AAT1 plays a pivotal role in chloroquine resistance evolution in malaria parasites
Malaria parasites break down host hemoglobin 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 inPlasmodium falciparum, but typically 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 an amino acid transporter (pfaat1)S258<jats:underline>L</jats:underline>variant which increased from 0-87% in frequency between 1984 and 2014 in parallel withpfcrt1K76<jats:underline>T</jats:underline>. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containingpfaat1that is selected by CQ treatment. Gene editing demonstrated thatpfaat1S258<jats:underline>L</jats:underline>potentiates CQ-resistance but at a cost of reduced fitness, whilepfaat1F313<jats:underline>S</jats:underline>, a common Southeast Asian polymorphism, reduces CQ-resistance while restoring fitness. Our analyses reveal hidden complexity in CQ-resistance evolution, suggesting thatpfaat1may 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..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 14. Dez. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Amambua-Ngwa, Alfred [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.05.26.493611 |
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| PPN (Katalog-ID): |
XBI038159074 |
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| 245 | 1 | 0 | |a An amino acid transporter AAT1 plays a pivotal role in chloroquine resistance evolution in malaria parasites |
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| 520 | |a Malaria parasites break down host hemoglobin 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 inPlasmodium falciparum, but typically 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 an amino acid transporter (pfaat1)S258<jats:underline>L</jats:underline>variant which increased from 0-87% in frequency between 1984 and 2014 in parallel withpfcrt1K76<jats:underline>T</jats:underline>. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containingpfaat1that is selected by CQ treatment. Gene editing demonstrated thatpfaat1S258<jats:underline>L</jats:underline>potentiates CQ-resistance but at a cost of reduced fitness, whilepfaat1F313<jats:underline>S</jats:underline>, a common Southeast Asian polymorphism, reduces CQ-resistance while restoring fitness. Our analyses reveal hidden complexity in CQ-resistance evolution, suggesting thatpfaat1may 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. | ||
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| 700 | 1 | |a Button-Simons, Katrina A. |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xue |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Sudhir |e verfasserin |4 aut | |
| 700 | 1 | |a Brenneman, Katelyn Vendrely |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrari, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Checkley, Lisa A. |e verfasserin |4 aut | |
| 700 | 1 | |a Haile, Meseret T. |e verfasserin |4 aut | |
| 700 | 1 | |a Shoue, Douglas A. |e verfasserin |4 aut | |
| 700 | 1 | |a McDew-White, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Tindall, Sarah M. |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes, Ann |e verfasserin |4 aut | |
| 700 | 1 | |a Delgado, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Dalhoff, Haley |e verfasserin |4 aut | |
| 700 | 1 | |a Larbalestier, James K. |e verfasserin |4 aut | |
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| 700 | 1 | |a D’Alessandro, Umberto |e verfasserin |4 aut | |
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