Uptake and metabolism of arginine impact Plasmodium development in the liver

Patrícia Meireles,Bryan C Mounce,Rita I Aroeira,António M Mendes,Marco Vignuzzi,Miguel Prudêncio,Henry M Staines

doi:10.1038/s41598-017-04424-y

Patrícia Meireles, Bryan C Mounce + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-04424-y

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Abstract

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.

Highlights

Malaria remains one of the most prevalent infectious diseases worldwide
Our results reveal an important role for the CAT2A/B transporters in the uptake of Arg by infected hepatic cells and show that Arg-dependent polyamine biosynthesis plays an essential role in the development of hepatic parasites
In light of our previous microarray results, which have shown that the expression of the gene encoding CAT2A and CAT2B, SLC7A2, is upregulated during the initial phase of infection of hepatoma cells by P. berghei parasites[23], we decided to investigate the functional role of this transporter during the liver stage of the Plasmodium life cycle

Summary

Introduction

Malaria remains one of the most prevalent infectious diseases worldwide It is caused by protozoan parasites of the genus Plasmodium that enter their mammalian host in the form of sporozoites, via the bite of an infected Anopheles mosquito. Cationic amino acids, including L-arginine (Arg), are transported through biological membranes by various distinct transport systems[4, 5]. Arg can be metabolized via multiple pathways that are initiated by arginase, nitric oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase These pathways produce polyamines, nitric oxide (NO), proline, glutamate, creatine, and agmatine, each of which has great biological importance (reviewed in refs 12 and 13). Our results reveal an important role for the CAT2A/B transporters in the uptake of Arg by infected hepatic cells and show that Arg-dependent polyamine biosynthesis plays an essential role in the development of hepatic parasites

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