Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development

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 m...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	host-pathogen interaction Leishmania amino acid sensing amino acid transport intracellular parasitism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e194efdd6f54cbbaf5c38700237ad61
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spelling	oai:doaj.org-article:0e194efdd6f54cbbaf5c38700237ad612021-11-15T16:19:09ZSensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development10.1128/mBio.02023-202150-7511https://doaj.org/article/0e194efdd6f54cbbaf5c38700237ad612020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02023-20https://doaj.org/toc/2150-7511ABSTRACT 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.Adele Goldman-PinkovichSriram KannanRoni Nitzan-KorenMadhu PuriHarsh PawarYael Bar-AvrahamJacquelyn McDonaldAakash SurWen-Wei ZhangGreg MatlashewskiRentala MadhubalaShulamit MichaeliPeter J. MylerDan ZilbersteinAmerican Society for Microbiologyarticlehost-pathogen interactionLeishmaniaamino acid sensingamino acid transportintracellular parasitismMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	host-pathogen interaction Leishmania amino acid sensing amino acid transport intracellular parasitism Microbiology QR1-502
spellingShingle	host-pathogen interaction Leishmania amino acid sensing amino acid transport intracellular parasitism Microbiology QR1-502 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 Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development
description	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.
format	article
author	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
author_facet	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
author_sort	Adele Goldman-Pinkovich
title	Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development
title_short	Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development
title_full	Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development
title_fullStr	Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development
title_full_unstemmed	Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development
title_sort	sensing host arginine is essential for <italic toggle="yes">leishmania</italic> parasites’ intracellular development
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/0e194efdd6f54cbbaf5c38700237ad61
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Sensing Host Arginine Is Essential for <italic toggle="yes">Leishmania</italic> Parasites’ Intracellular Development

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