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

PLoS Pathog. 2016 Apr 4;12(4):e1005494. doi: 10.1371/journal.ppat.1005494. eCollection 2016 Apr.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / metabolism
  • Cell Line
  • Humans
  • Leishmania donovani / physiology*
  • Macrophages / metabolism*
  • Membrane Transport Proteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phagosomes / metabolism
  • Polyamines / metabolism


  • Membrane Transport Proteins
  • Polyamines
  • Arginine
  • Mitogen-Activated Protein Kinases

Grant support

This work was supported by grant number 696-12 from the Israel Science Foundation (Figs 1–5 and Table 2; and by grant number 2009226 from the U.S.-Israel binational Science Foundation (Table 1; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.