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The hunger games: sensing host arginine is essential for Leishmania parasite virulence

Adele Goldman-Pinkovich, Sriram Kannan, Roni Nitzan-Koren, Madhu Puri, Yael Bar-Avraham, Jacqueline A. McDonald, Aakash Sur, Wen-Wei Zhang, Greg Matlashewski, Rentala Madhubala, Shulamit Michaeli, Peter J. Myler, Dan Zilberstein
doi: https://doi.org/10.1101/751610
Adele Goldman-Pinkovich
1Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
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Sriram Kannan
2The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan Israel
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Roni Nitzan-Koren
1Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
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Madhu Puri
3School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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Yael Bar-Avraham
1Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
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Jacqueline A. McDonald
4Center for Global Infectious Disease Research, Seattle Children’s Research Institute, USA
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Aakash Sur
4Center for Global Infectious Disease Research, Seattle Children’s Research Institute, USA
5Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, USA
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Wen-Wei Zhang
6Department of Microbiology and Immunology, McGill University, Montreal, Canada
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Greg Matlashewski
6Department of Microbiology and Immunology, McGill University, Montreal, Canada
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Rentala Madhubala
3School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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Shulamit Michaeli
2The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan Israel
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Peter J. Myler
4Center for Global Infectious Disease Research, Seattle Children’s Research Institute, USA
5Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, USA
7Department of Global Health, University of Washington, Seattle, USA
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Dan Zilberstein
1Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
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  • For correspondence: danz@technion.ac.il
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Abstract

Arginine homeostasis in lysosomes is critical for growth and metabolism of mammalian cells. They employ a specific sensor (SLC38A9) that monitors intra-lysosome arginine sufficiency and subsequently up-regulates cellular mTORC1 activity. Lysosomes of macrophages (phagolysosomes) are the niche where the parasitic protozoan Leishmania resides and causes important human disease. Several years ago, we discovered that upon arginine starvation, cultured Leishmania parasites promptly activate a MAPK2-mediated Arginine Deprivation Response (ADR) pathway, resulting in up-regulation of the Leishmania arginine transporter (AAP3), as well as a small group of other transporters. Significantly, ADR is also activated during macrophage infection, implying that the intracellular parasite actively depletes arginine within the host phagolysosome, likely to prevent mTORC1 activation and enhance intracellular development. We hypothesize that ADR-mediated up-regulation of AAP3 activity is necessary to withstand the resultant arginine starvation. Both copies of the AAP3 genes are located (in tandem) on a tetrasomic chromosome (chr31), but only one (AAP3.2) is responsive to arginine deprivation. CRISPR/Cas9-mediated disruption of the AAP3 locus yielded mutants that retain a basal level of arginine transport (mediated by AAP3.1), but lack a functional copy of AAP3.2 and are therefore not responsive to arginine starvation. While these mutants grow normally in culture as promastigotes, they were impaired in their ability to develop inside THP1 macrophages grown under physiological concentrations of arginine (0.1 mM). However, flooding the macrophage growth medium with arginine (1.5 mM) restored parasite infectivity and intracellular growth to that of wild type. The results indicate that inside the host macrophage, Leishmania must overcome the arginine “Hunger Games” by up-regulating transport of arginine via the ADR. Furthermore, the AAP3.2 mutants were ~70-80% less virulent in Balb/C mice, showing, for the first time, that the ability to monitor and respond to changes in host metabolite levels is essential for pathogenesis.

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Posted August 30, 2019.
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The hunger games: sensing host arginine is essential for Leishmania parasite virulence
Adele Goldman-Pinkovich, Sriram Kannan, Roni Nitzan-Koren, Madhu Puri, Yael Bar-Avraham, Jacqueline A. McDonald, Aakash Sur, Wen-Wei Zhang, Greg Matlashewski, Rentala Madhubala, Shulamit Michaeli, Peter J. Myler, Dan Zilberstein
bioRxiv 751610; doi: https://doi.org/10.1101/751610
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The hunger games: sensing host arginine is essential for Leishmania parasite virulence
Adele Goldman-Pinkovich, Sriram Kannan, Roni Nitzan-Koren, Madhu Puri, Yael Bar-Avraham, Jacqueline A. McDonald, Aakash Sur, Wen-Wei Zhang, Greg Matlashewski, Rentala Madhubala, Shulamit Michaeli, Peter J. Myler, Dan Zilberstein
bioRxiv 751610; doi: https://doi.org/10.1101/751610

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