MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects

ABSTRACT The obligate intracellular parasite Toxoplasma gondii controls its host cell from within the parasitophorous vacuole (PV) by using a number of diverse effector proteins, a subset of which require the aspartyl protease 5 enzyme (ASP5) and/or the recently discovered MYR1 protein to cross the...

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Autores principales:	Adit Naor, Michael W. Panas, Nicole Marino, Michael J. Coffey, Christopher J. Tonkin, John C. Boothroyd
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Toxoplasma gondii effector functions host response host-parasite relationship Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7435798edd5842b18076726fbe510eb7
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spelling	oai:doaj.org-article:7435798edd5842b18076726fbe510eb72021-11-15T15:53:26ZMYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects10.1128/mBio.02401-172150-7511https://doaj.org/article/7435798edd5842b18076726fbe510eb72018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02401-17https://doaj.org/toc/2150-7511ABSTRACT The obligate intracellular parasite Toxoplasma gondii controls its host cell from within the parasitophorous vacuole (PV) by using a number of diverse effector proteins, a subset of which require the aspartyl protease 5 enzyme (ASP5) and/or the recently discovered MYR1 protein to cross the PV membrane. To examine the impact these effectors have in the context of the entirety of the host response to Toxoplasma, we used RNA-Seq to analyze the transcriptome expression profiles of human foreskin fibroblasts infected with wild-type RH (RH-WT), RHΔmyr1, and RHΔasp5 tachyzoites. Interestingly, the majority of the differentially regulated genes responding to Toxoplasma infection are MYR1 dependent. A subset of MYR1 responses were ASP5 independent, and MYR1 function did not require ASP5 cleavage, suggesting the export of some effectors requires only MYR1. Gene set enrichment analysis of MYR1-dependent host responses suggests an upregulation of E2F transcription factors and the cell cycle and a downregulation related to interferon signaling, among numerous others. Most surprisingly, “hidden” responses arising in RHΔmyr1- but not RH-WT-infected host cells indicate counterbalancing actions of MYR1-dependent and -independent activities. The host genes and gene sets revealed here to be MYR1 dependent provide new insight into the parasite’s ability to co-opt host cell functions. IMPORTANCE Toxoplasma gondii is unique in its ability to successfully invade and replicate in a broad range of host species and cells within those hosts. The complex interplay of effector proteins exported by Toxoplasma is key to its success in co-opting the host cell to create a favorable replicative niche. Here we show that a majority of the transcriptomic effects in tachyzoite-infected cells depend on the activity of a novel translocation system involving MYR1 and that the effectors delivered by this system are part of an intricate interplay of activators and suppressors. Removal of all MYR1-dependent effectors reveals previously unknown activities that are masked or hidden by the action of these proteins.Adit NaorMichael W. PanasNicole MarinoMichael J. CoffeyChristopher J. TonkinJohn C. BoothroydAmerican Society for MicrobiologyarticleToxoplasma gondiieffector functionshost responsehost-parasite relationshipMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma gondii effector functions host response host-parasite relationship Microbiology QR1-502
spellingShingle	Toxoplasma gondii effector functions host response host-parasite relationship Microbiology QR1-502 Adit Naor Michael W. Panas Nicole Marino Michael J. Coffey Christopher J. Tonkin John C. Boothroyd MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects
description	ABSTRACT The obligate intracellular parasite Toxoplasma gondii controls its host cell from within the parasitophorous vacuole (PV) by using a number of diverse effector proteins, a subset of which require the aspartyl protease 5 enzyme (ASP5) and/or the recently discovered MYR1 protein to cross the PV membrane. To examine the impact these effectors have in the context of the entirety of the host response to Toxoplasma, we used RNA-Seq to analyze the transcriptome expression profiles of human foreskin fibroblasts infected with wild-type RH (RH-WT), RHΔmyr1, and RHΔasp5 tachyzoites. Interestingly, the majority of the differentially regulated genes responding to Toxoplasma infection are MYR1 dependent. A subset of MYR1 responses were ASP5 independent, and MYR1 function did not require ASP5 cleavage, suggesting the export of some effectors requires only MYR1. Gene set enrichment analysis of MYR1-dependent host responses suggests an upregulation of E2F transcription factors and the cell cycle and a downregulation related to interferon signaling, among numerous others. Most surprisingly, “hidden” responses arising in RHΔmyr1- but not RH-WT-infected host cells indicate counterbalancing actions of MYR1-dependent and -independent activities. The host genes and gene sets revealed here to be MYR1 dependent provide new insight into the parasite’s ability to co-opt host cell functions. IMPORTANCE Toxoplasma gondii is unique in its ability to successfully invade and replicate in a broad range of host species and cells within those hosts. The complex interplay of effector proteins exported by Toxoplasma is key to its success in co-opting the host cell to create a favorable replicative niche. Here we show that a majority of the transcriptomic effects in tachyzoite-infected cells depend on the activity of a novel translocation system involving MYR1 and that the effectors delivered by this system are part of an intricate interplay of activators and suppressors. Removal of all MYR1-dependent effectors reveals previously unknown activities that are masked or hidden by the action of these proteins.
format	article
author	Adit Naor Michael W. Panas Nicole Marino Michael J. Coffey Christopher J. Tonkin John C. Boothroyd
author_facet	Adit Naor Michael W. Panas Nicole Marino Michael J. Coffey Christopher J. Tonkin John C. Boothroyd
author_sort	Adit Naor
title	MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects
title_short	MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects
title_full	MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects
title_fullStr	MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects
title_full_unstemmed	MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects
title_sort	myr1-dependent effectors are the major drivers of a host cell’s early response to <italic toggle="yes">toxoplasma</italic>, including counteracting myr1-independent effects
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/7435798edd5842b18076726fbe510eb7
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MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to <italic toggle="yes">Toxoplasma</italic>, Including Counteracting MYR1-Independent Effects

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