Sensing host arginine is essential for leishmania parasites’ intracellular development

Adele Goldman-Pinkovich, Sriram Kannan, Roni Nitzan-Koren, Madhu Puri, Harsh Pawar, Yael Bar-Avraham, Jacquelyn McDonald, Aakash Sur, Wen Wei Zhang, Greg Matlashewski, Rentala Madhubala, Shulamit Michaeli, Peter J. Myler, Dan Zilberstein

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 in-fection, 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, imply-ing that arginine levels within the host phagolysosome are limiting for growth. We hypothesize that ADR-mediated upregulation of AAP3 activity is necessary to with-stand 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 me-tabolite 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 in-fection, 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.

Original languageEnglish
Article numbere02023-20
Pages (from-to)1-13
Number of pages13
JournalmBio
Volume11
Issue number5
DOIs
StatePublished - 13 Oct 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 Goldman-Pinkovich et al.

Funding

We thank Ido Izhaki of Haifa University for his help with the statistical analyses. We also thank Michal Almoznino for experimental analyses. Funding for this work was provided by University Grant Commission (UGC)-Israel Science Foundation (Indo-Israel) research grant no. 2316/15 to D.Z., A.G.-P., and R.M. and USA-Israel Binational Foundation grant no. 2017030 to D.Z. and P.J.M. Funding for this work was provided by University Grant Commission (UGC)-Israel Science Foundation (Indo-Israel) research grant no. 2316/15 to D.Z., A.G.-P., and R.M. and USA-Israel Binational Foundation grant no. 2017030 to D.Z. and P.J.M.

FundersFunder number
USA-Israel Binational Foundation2017030
University Grant Commission
University Grants Commission
Israel Science Foundation2316/15

    Keywords

    • Amino acid sensing
    • Amino acid transport
    • Host-pathogen interaction
    • Intracellular parasitism
    • Leishmania

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