<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

ABSTRACT Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein respon...

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Autores principales:	Leonardo Augusto, Jennifer Martynowicz, Parth H. Amin, Nada S. Alakhras, Mark H. Kaplan, Ronald C. Wek, William J. Sullivan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Toxoplasma parasites UPR IRE1 PERK cell migration Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3d630c390fc84de5b6a66b41628efa5f
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spelling	oai:doaj.org-article:3d630c390fc84de5b6a66b41628efa5f2021-11-15T15:56:43Z<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells10.1128/mBio.00915-202150-7511https://doaj.org/article/3d630c390fc84de5b6a66b41628efa5f2020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00915-20https://doaj.org/toc/2150-7511ABSTRACT Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis. IMPORTANCE Cells that are infected with the parasite Toxoplasma gondii exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this report, we identify a new mechanism used by Toxoplasma to hijack its host cell and increase its mobility. We further show that the ability of Toxoplasma to increase host cell migration involves not the enzymatic activity of IRE1 but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly hinders dissemination of Toxoplasma in vivo. Our findings reveal a new mechanism underlying host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent infection around the body.Leonardo AugustoJennifer MartynowiczParth H. AminNada S. AlakhrasMark H. KaplanRonald C. WekWilliam J. SullivanAmerican Society for MicrobiologyarticleToxoplasmaparasitesUPRIRE1PERKcell migrationMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma parasites UPR IRE1 PERK cell migration Microbiology QR1-502
spellingShingle	Toxoplasma parasites UPR IRE1 PERK cell migration Microbiology QR1-502 Leonardo Augusto Jennifer Martynowicz Parth H. Amin Nada S. Alakhras Mark H. Kaplan Ronald C. Wek William J. Sullivan <named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
description	ABSTRACT Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis. IMPORTANCE Cells that are infected with the parasite Toxoplasma gondii exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this report, we identify a new mechanism used by Toxoplasma to hijack its host cell and increase its mobility. We further show that the ability of Toxoplasma to increase host cell migration involves not the enzymatic activity of IRE1 but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly hinders dissemination of Toxoplasma in vivo. Our findings reveal a new mechanism underlying host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent infection around the body.
format	article
author	Leonardo Augusto Jennifer Martynowicz Parth H. Amin Nada S. Alakhras Mark H. Kaplan Ronald C. Wek William J. Sullivan
author_facet	Leonardo Augusto Jennifer Martynowicz Parth H. Amin Nada S. Alakhras Mark H. Kaplan Ronald C. Wek William J. Sullivan
author_sort	Leonardo Augusto
title	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
title_short	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
title_full	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
title_fullStr	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
title_full_unstemmed	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
title_sort	<named-content content-type="genus-species">toxoplasma gondii</named-content> co-opts the unfolded protein response to enhance migration and dissemination of infected host cells
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/3d630c390fc84de5b6a66b41628efa5f
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<named-content content-type="genus-species">Toxoplasma gondii</named-content> Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

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