Sequestration and metabolism of host cell arginine by the intraerythrocytic malaria parasite<i>Plasmodium falciparum</i>

Cobbold, Simon A.; Llinás, Manuel; Kirk, Kiaran

doi:10.1111/cmi.12552

Cited by 19 publications

(19 citation statements)

References 45 publications

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“…However, the protein has not been subject to detailed study and its function is not previously established. Function could not be detected following heterologous expression in Xenopus laevis oocytes 29 , in contrast to the yeast expression system described here. Reasons for this difference may include differences in protein folding or localization in the two expression systems.…”

Section: Discussioncontrasting

confidence: 81%

“…It transpires that this homologue is a putative amino acid transporter in which SNPs were previously linked to chloroquine resistance in malaria parasites 27 , 28 . A recent attempt at characterisation by heterologous expression in Xenopus laevis oocytes did not produce detectably-functional protein 29 . Here we successfully apply a yeast heterologous expression system to show that the parasite protein mediates uptake of quinoline drugs so altering the level of drug resistance.…”

Section: Introductionmentioning

confidence: 97%

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Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials

Tindall

Vallières

Lakhani

et al. 2018

Sci Rep

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Antimalarial drug resistance hampers effective malaria treatment. Critical SNPs in a particular, putative amino acid transporter were recently linked to chloroquine (CQ) resistance in malaria parasites. Here, we show that this conserved protein (PF3D7_0629500 in Plasmodium falciparum; AAT1 in P. chabaudi) is a structural homologue of the yeast amino acid transporter Tat2p, which is known to mediate quinine uptake and toxicity. Heterologous expression of PF3D7_0629500 in yeast produced CQ hypersensitivity, coincident with increased CQ uptake. PF3D7_0629500-expressing cultures were also sensitized to related antimalarials; amodiaquine, mefloquine and particularly quinine. Drug sensitivity was reversed by introducing a SNP linked to CQ resistance in the parasite. Like Tat2p, PF3D7_0629500-dependent quinine hypersensitivity was suppressible with tryptophan, consistent with a common transport mechanism. A four-fold increase in quinine uptake by PF3D7_0629500 expressing cells was abolished by the resistance SNP. The parasite protein localised primarily to the yeast plasma membrane. Its expression varied between cells and this heterogeneity was used to show that high-expressing cell subpopulations were the most drug sensitive. The results reveal that the PF3D7_0629500 protein can determine the level of sensitivity to several major quinine-related antimalarials through an amino acid-inhibitable drug transport function. The potential clinical relevance is discussed.

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Section: Discussioncontrasting

confidence: 81%

Section: Introductionmentioning

confidence: 97%

Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials

Tindall

Vallières

Lakhani

et al. 2018

Sci Rep

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“…The functional characteristics of Pb NPT1 expressed in Xenopus oocytes are very similar to those of the pathway mediating the uptake of arginine into P. falciparum parasites 31 , consistent with the P. falciparum orthologue of Pb NPT1 (PF3D7_0104800) serving as the major arginine transporter in asexual-stage P. falciparum parasites. P. falciparum infection causes depletion of arginine in the host erythrocyte 31 , and Plasmodium infection leads to hypoargininaemia, a depletion of arginine in the plasma of the host that contributes to poor disease outcomes such as cerebral malaria 33 34 . Plasmodium NPT1 conceivably plays a role in Plasmodium -induced hypoargininaemia.…”

Section: Resultssupporting

confidence: 63%

“…Intraerythrocytic asexual stages of the human malaria parasite P. falciparum have been shown to take up exogenous arginine via an unidentified pathway that is inhibited by other cationic amino acids 31 32 . The functional characteristics of Pb NPT1 expressed in Xenopus oocytes are very similar to those of the pathway mediating the uptake of arginine into P. falciparum parasites 31 , consistent with the P. falciparum orthologue of Pb NPT1 (PF3D7_0104800) serving as the major arginine transporter in asexual-stage P. falciparum parasites. P. falciparum infection causes depletion of arginine in the host erythrocyte 31 , and Plasmodium infection leads to hypoargininaemia, a depletion of arginine in the plasma of the host that contributes to poor disease outcomes such as cerebral malaria 33 34 .…”

Section: Resultsmentioning

confidence: 99%

Cationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites

et al. 2017

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Apicomplexans are obligate intracellular parasites that scavenge essential nutrients from their hosts via transporter proteins on their plasma membrane. The identities of the transporters that mediate amino acid uptake into apicomplexans are unknown. Here we demonstrate that members of an apicomplexan-specific protein family—the Novel Putative Transporters (NPTs)—play key roles in the uptake of cationic amino acids. We show that an NPT from Toxoplasma gondii (TgNPT1) is a selective arginine transporter that is essential for parasite survival and virulence. We also demonstrate that a homologue of TgNPT1 from the malaria parasite Plasmodium berghei (PbNPT1), shown previously to be essential for the sexual gametocyte stage of the parasite, is a cationic amino acid transporter. This reveals a role for cationic amino acid scavenging in gametocyte biology. Our study demonstrates a critical role for amino acid transporters in the survival, virulence and life cycle progression of these parasites.

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“…Recently, it has further been shown that, following erythrocyte invasion by P . falciparum , the Arg pool in the host compartment is sequestered and metabolized by the parasite into citrulline and ornithine 41 . Of note, polyamines have been shown to be among the major metabolites present within blood-stage P .…”

Section: Discussionmentioning

confidence: 99%

Uptake and metabolism of arginine impact Plasmodium development in the liver

Meireles

Mendes

Aroeira

et al. 2017

Sci Rep

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Prior to infecting erythrocytes and causing malaria symptoms, Plasmodium parasites undergo an obligatory phase of invasion and extensive replication inside their mammalian host’s liver cells that depends on the parasite’s ability to obtain the nutrients it requires for its intra-hepatic growth and multiplication. Here, we show that L-arginine (Arg) uptake through the host cell’s SLC7A2-encoded transporters is essential for the parasite’s development and maturation in the liver. Our data suggest that the Arg that is taken up is primarily metabolized by the arginase pathway to produce the polyamines required for Plasmodium growth. Although the parasite may hijack the host’s biosynthesis pathway, it relies mainly upon its own arginase-AdoMetDC/ODC pathway to acquire the polyamines it needs to develop. These results identify for the first time a pivotal role for Arg-dependent polyamine production during Plasmodium’s hepatic development and pave the way to the exploitation of strategies to impact liver infection by the malaria parasite through the modulation of Arg uptake and polyamine synthesis.

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Sequestration and metabolism of host cell arginine by the intraerythrocytic malaria parasitePlasmodium falciparum

Cited by 19 publications

References 45 publications

Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials

Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials

Cationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites

Uptake and metabolism of arginine impact Plasmodium development in the liver

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