<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon

ABSTRACT Toxoplasma gondii evades host immunity to establish a chronic infection. Here, we assessed the role of parasitophorous vacuole (PV) membrane (PVM)- and intravacuolar network (IVN) membrane-localized dense granule (GRA) proteins in the development of acute and chronic Toxoplasma infection. D...

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Autores principales:	Barbara A. Fox, Rebekah B. Guevara, Leah M. Rommereim, Alejandra Falla, Valeria Bellini, Graciane Pètre, Camille Rak, Viviana Cantillana, Jean-François Dubremetz, Marie-France Cesbron-Delauw, Gregory A. Taylor, Corinne Mercier, David J. Bzik
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Toxoplasma gondii chronic infection dense granule innate immunity membrane proteins virulence factors Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ef77c5b30b284e599b6b47cf0cdd3e64
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spelling	oai:doaj.org-article:ef77c5b30b284e599b6b47cf0cdd3e642021-11-15T16:22:11Z<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon10.1128/mBio.00589-192150-7511https://doaj.org/article/ef77c5b30b284e599b6b47cf0cdd3e642019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00589-19https://doaj.org/toc/2150-7511ABSTRACT Toxoplasma gondii evades host immunity to establish a chronic infection. Here, we assessed the role of parasitophorous vacuole (PV) membrane (PVM)- and intravacuolar network (IVN) membrane-localized dense granule (GRA) proteins in the development of acute and chronic Toxoplasma infection. Deletion of PVM-associated GRA3, GRA7, GRA8, and GRA14 or IVN membrane-associated GRA2, GRA9, and GRA12 in the low-virulence type II Prugniaud (Pru) strain induced severe defects in the development of chronic-stage cysts in vivo without affecting the parasite growth rate or the ability to differentiate into cysts in vitro. Acute virulence of the PruΔgra2, PruΔgra3, and PruΔgra4 mutants was reduced but not abolished. In contrast, the PruΔgra12 mutant was avirulent in mice and PruΔgra12 parasites failed to establish a chronic infection. High-virulence type I strain RHΔgra12 parasites also exhibited a major defect in acute virulence. In gamma interferon (IFN-γ)-activated macrophages, type I RHΔgra12 and type II PruΔgra12 parasites resisted the coating of the PVM with host immunity-related GTPases as effectively as the parental type I RHΔku80 and type II PruΔku80 strains, respectively. Despite this resistance, Δgra12 PVs ultimately succumbed to IFN-γ-activated host cell innate immunity. Our findings uncover a key role for GRA12 in mediating resistance to host IFN-γ and reveal that many other IVN membrane-associated GRA proteins, as well as PVM-localized GRA proteins, play important roles in establishing chronic infection. IMPORTANCE Toxoplasma gondii cysts reactivate during immune deficiency and cause fatal encephalitis. Parasite molecules that coordinate the development of acute and chronic infection are poorly characterized. Here, we show that many intravacuolar network membrane and parasitophorous vacuole membrane-associated dense granule (GRA) proteins orchestrate the development of chronic cysts in vivo. A subset of these GRA proteins also modulate acute virulence, and one protein that associates with the intravacuolar network membranes, namely GRA12, was identified as a major virulence factor required for parasite resistance to host gamma interferon (IFN-γ). Our results revealed that many parasitophorous vacuole membrane and intravacuolar network membrane-associated GRA proteins are essential for successful chronic infection.Barbara A. FoxRebekah B. GuevaraLeah M. RommereimAlejandra FallaValeria BelliniGraciane PètreCamille RakViviana CantillanaJean-François DubremetzMarie-France Cesbron-DelauwGregory A. TaylorCorinne MercierDavid J. BzikAmerican Society for MicrobiologyarticleToxoplasma gondiichronic infectiondense granuleinnate immunitymembrane proteinsvirulence factorsMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma gondii chronic infection dense granule innate immunity membrane proteins virulence factors Microbiology QR1-502
spellingShingle	Toxoplasma gondii chronic infection dense granule innate immunity membrane proteins virulence factors Microbiology QR1-502 Barbara A. Fox Rebekah B. Guevara Leah M. Rommereim Alejandra Falla Valeria Bellini Graciane Pètre Camille Rak Viviana Cantillana Jean-François Dubremetz Marie-France Cesbron-Delauw Gregory A. Taylor Corinne Mercier David J. Bzik <named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon
description	ABSTRACT Toxoplasma gondii evades host immunity to establish a chronic infection. Here, we assessed the role of parasitophorous vacuole (PV) membrane (PVM)- and intravacuolar network (IVN) membrane-localized dense granule (GRA) proteins in the development of acute and chronic Toxoplasma infection. Deletion of PVM-associated GRA3, GRA7, GRA8, and GRA14 or IVN membrane-associated GRA2, GRA9, and GRA12 in the low-virulence type II Prugniaud (Pru) strain induced severe defects in the development of chronic-stage cysts in vivo without affecting the parasite growth rate or the ability to differentiate into cysts in vitro. Acute virulence of the PruΔgra2, PruΔgra3, and PruΔgra4 mutants was reduced but not abolished. In contrast, the PruΔgra12 mutant was avirulent in mice and PruΔgra12 parasites failed to establish a chronic infection. High-virulence type I strain RHΔgra12 parasites also exhibited a major defect in acute virulence. In gamma interferon (IFN-γ)-activated macrophages, type I RHΔgra12 and type II PruΔgra12 parasites resisted the coating of the PVM with host immunity-related GTPases as effectively as the parental type I RHΔku80 and type II PruΔku80 strains, respectively. Despite this resistance, Δgra12 PVs ultimately succumbed to IFN-γ-activated host cell innate immunity. Our findings uncover a key role for GRA12 in mediating resistance to host IFN-γ and reveal that many other IVN membrane-associated GRA proteins, as well as PVM-localized GRA proteins, play important roles in establishing chronic infection. IMPORTANCE Toxoplasma gondii cysts reactivate during immune deficiency and cause fatal encephalitis. Parasite molecules that coordinate the development of acute and chronic infection are poorly characterized. Here, we show that many intravacuolar network membrane and parasitophorous vacuole membrane-associated dense granule (GRA) proteins orchestrate the development of chronic cysts in vivo. A subset of these GRA proteins also modulate acute virulence, and one protein that associates with the intravacuolar network membranes, namely GRA12, was identified as a major virulence factor required for parasite resistance to host gamma interferon (IFN-γ). Our results revealed that many parasitophorous vacuole membrane and intravacuolar network membrane-associated GRA proteins are essential for successful chronic infection.
format	article
author	Barbara A. Fox Rebekah B. Guevara Leah M. Rommereim Alejandra Falla Valeria Bellini Graciane Pètre Camille Rak Viviana Cantillana Jean-François Dubremetz Marie-France Cesbron-Delauw Gregory A. Taylor Corinne Mercier David J. Bzik
author_facet	Barbara A. Fox Rebekah B. Guevara Leah M. Rommereim Alejandra Falla Valeria Bellini Graciane Pètre Camille Rak Viviana Cantillana Jean-François Dubremetz Marie-France Cesbron-Delauw Gregory A. Taylor Corinne Mercier David J. Bzik
author_sort	Barbara A. Fox
title	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon
title_short	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon
title_full	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon
title_fullStr	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon
title_full_unstemmed	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon
title_sort	<named-content content-type="genus-species">toxoplasma gondii</named-content> parasitophorous vacuole membrane-associated dense granule proteins orchestrate chronic infection and gra12 underpins resistance to host gamma interferon
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ef77c5b30b284e599b6b47cf0cdd3e64
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<named-content content-type="genus-species">Toxoplasma gondii</named-content> Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon

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