Abstract
Arginine homeostasis in lysosomes is critical for the growth and metabolism of mammalian cells. Phagolysosomes of macrophages are the niche where the parasitic protozoan Leishmania resides and causes human leishmaniasis. During infection, parasites encounter arginine deprivation, which is monitored by a sensor on the parasite cell surface. The sensor promptly activates a mitogen-activated protein kinase 2 (MAPK2)-mediated arginine deprivation response (ADR) pathway, resulting in upregulating the abundance and activity of the Leishmania arginine transporter (AAP3). Significantly, the ADR is also activated during macrophage infection, implying that arginine levels within the host phagolysosome are limiting for growth. We hypothesize that ADR-mediated upregulation of AAP3 activity is necessary to withstand arginine starvation, suggesting that the ADR is essential for parasite intracellular development. CRISPR/Cas9-mediated disruption of the AAP3 locus yielded mutants that retain a basal level of arginine transport but lack the ability to respond to arginine starvation. While these mutants grow normally in culture, they were impaired in their ability to develop inside THP-1 macrophages and were ∼70 to 80% less infective in BALB/c mice. Hence, inside the host macrophage, Leishmania must overcome the arginine "hunger games" by upregulating the transport of arginine via the ADR. We show that the ability to monitor and respond to changes in host metabolite levels is essential for pathogenesis.IMPORTANCE In this study, we report that the ability of the human pathogen Leishmania to sense and monitor the lack of arginine in the phagolysosome of the host macrophage is essential for disease development. Phagolysosomes of macrophages are the niche where Leishmania resides and causes human leishmaniasis. During infection, the arginine concentration in the phagolysosome decreases as part of the host innate immune response. An arginine sensor on the Leishmania cell surface activates an arginine deprivation response pathway that upregulates the expression of a parasite arginine transporter (AAP3). Here, we use CRISPR/Cas9-mediated disruption of the AAP3 locus to show that this response enables Leishmania parasites to successfully compete with the host macrophage in the "hunger games" for arginine.
Highlights
Arginine homeostasis in lysosomes is critical for the growth and metabolism of mammalian cells
A few years ago, we discovered that upon arginine starvation, Leishmania parasites promptly activate a mitogen-activated protein kinase 2 (MAPK2)-mediated arginine deprivation response (ADR) pathway, resulting in the upregulation of the expression and activity of the Leishmania arginine transporter (AAP3) [11]
To assess whether the AAP3.2 response to arginine deprivation is necessary for parasite intracellular development, we aimed to delete it from the L. donovani genome
Summary
Arginine homeostasis in lysosomes is critical for the growth and metabolism of mammalian cells. The reduction of the host arginine pool becomes a doubleedged sword for Leishmania parasites in infected macrophages since they cannot synthesize arginine de novo Instead, they must import exogenous arginine via a monospecific amino acid transporter (AAP3) [9], using it primarily in the polyamine pathway to provide precursors for trypanothione biosynthesis [10]. They must import exogenous arginine via a monospecific amino acid transporter (AAP3) [9], using it primarily in the polyamine pathway to provide precursors for trypanothione biosynthesis [10] They encounter an intriguing metabolic dilemma: on the one hand, emptying the host arginine pool provides an advantage (reduction of NO), but at the same time, it causes a potentially deadly disadvantage by blocking the supply of an essential amino acid [8]. To survive, Leishmania parasites need to sense and respond to changes in arginine availability
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