An Arginine Deprivation Response Pathway Is Induced in Leishmania during Macrophage Invasion.

Adele Goldman-Pinkovich,Keren Bendelak,Rona Strasser,Doris Rentsch,Peter J Myler,Martin Wiese,Michal Zeituni-Molad,Moshe Ephros,Dan Zilberstein,Armando Jardim,Caitlin Balno,Ingrid Müller

doi:10.1371/journal.ppat.1005494

Abstract

Amino acid sensing is an intracellular function that supports nutrient homeostasis, largely through controlled release of amino acids from lysosomal pools. The intracellular pathogen Leishmania resides and proliferates within human macrophage phagolysosomes. Here we describe a new pathway in Leishmania that specifically senses the extracellular levels of arginine, an amino acid that is essential for the parasite. During infection, the macrophage arginine pool is depleted due to its use to produce metabolites (NO and polyamines) that constitute part of the host defense response and its suppression, respectively. We found that parasites respond to this shortage of arginine by up-regulating expression and activity of the Leishmania arginine transporter (LdAAP3), as well as several other transporters. Our analysis indicates the parasite monitors arginine levels in the environment rather than the intracellular pools. Phosphoproteomics and genetic analysis indicates that the arginine-deprivation response is mediated through a mitogen-activated protein kinase-2-dependent signaling cascade.

Highlights

Protozoan parasites of the genus Leishmania are causative agents of a wide spectrum of human and veterinary diseases, with clinical manifestations ranging from lesions of the skin and mucous membranes to lethal visceral disease [1]
Protozoa of the genus Leishmania are the causative agents of leishmaniasis in humans
These parasites cycle between promastigotes in the sand fly mid-gut and amastigotes in phagolysosome of mammalian macrophages

Summary

Introduction

Protozoan parasites of the genus Leishmania are causative agents of a wide spectrum of human and veterinary diseases, with clinical manifestations ranging from lesions of the skin and mucous membranes to lethal visceral disease [1]. Leishmania species cause morbidity and mortality throughout large areas of the Old and New World, with ~350 million people in 88 countries at risk of visceral leishmaniasis. Leishmania exhibit a digenetic life cycle including the extracellular promastigote and intracellular amastigote forms. Promastigote development occurs in the female sand fly alimentary tract, while differentiation into obligatory intracellular amastigotes occurs within the phagolysosome of mammalian macrophages [4, 5]. Intracellular differentiation is mimicked in axenic culture by shifting promastigotes from an insect-like (26°C, pH 7.4) to a lysosome-like (37°C, pH 5.5 and 5% CO2) environment [7,8,9]

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Conclusion