<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development

ABSTRACT Toxoplasma gondii is a protozoan parasite of great importance to human and animal health. In the host, this obligate intracellular parasite persists as a tissue cyst that is imperceptible to the immune response and unaffected by current therapies. The tissue cysts facilitate transmission th...

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Autores principales:	Sherri Huang, Michael J. Holmes, Joshua B. Radke, Dong-Pyo Hong, Ting-Kai Liu, Michael W. White, William J. Sullivan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	ApiAP2 apicomplexan parasites differentiation gene expression intracellular parasites transcription Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/45c1ca02eef54ef589b238165f1c8c0e
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spelling	oai:doaj.org-article:45c1ca02eef54ef589b238165f1c8c0e2021-11-15T15:21:45Z<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development10.1128/mSphere.00054-172379-5042https://doaj.org/article/45c1ca02eef54ef589b238165f1c8c0e2017-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00054-17https://doaj.org/toc/2379-5042ABSTRACT Toxoplasma gondii is a protozoan parasite of great importance to human and animal health. In the host, this obligate intracellular parasite persists as a tissue cyst that is imperceptible to the immune response and unaffected by current therapies. The tissue cysts facilitate transmission through predation and give rise to chronic cycles of toxoplasmosis in immunocompromised patients. Transcriptional changes accompany conversion of the rapidly replicating tachyzoites into the encysted bradyzoites, and yet the mechanisms underlying these alterations in gene expression are not well defined. Here we show that AP2IX-4 is a nuclear protein exclusively expressed in tachyzoites and bradyzoites undergoing division. Knockout of AP2IX-4 had no discernible effect on tachyzoite replication but resulted in a reduced frequency of tissue cyst formation following alkaline stress induction—a defect that is reversible by complementation. AP2IX-4 has a complex role in regulating bradyzoite gene expression, as the levels of many bradyzoite mRNAs dramatically increased beyond those seen under conditions of normal stress induction in AP2IX-4 knockout parasites exposed to alkaline media. The loss of AP2IX-4 also resulted in a modest virulence defect and reduced cyst burden in chronically infected mice, which was reversed by complementation. These findings illustrate that the transcriptional mechanisms responsible for tissue cyst development operate across the intermediate life cycle from the dividing tachyzoite to the dormant bradyzoite. IMPORTANCE Toxoplasma gondii is a single-celled parasite that persists in its host as a transmissible tissue cyst. How the parasite converts from its replicative form to the bradyzoites housed in tissue cysts is not well understood, but the process clearly involves changes in gene expression. Here we report that parasites lacking a cell cycle-regulated transcription factor called AP2IX-4 display reduced frequencies of tissue cyst formation in culture and in a mouse model of infection. Parasites missing AP2IX-4 lose the ability to regulate bradyzoite genes during tissue cyst development. Expressed in developing bradyzoites still undergoing division, AP2IX-4 may serve as a useful marker in the study of transitional forms of the parasite.Sherri HuangMichael J. HolmesJoshua B. RadkeDong-Pyo HongTing-Kai LiuMichael W. WhiteWilliam J. SullivanAmerican Society for MicrobiologyarticleApiAP2apicomplexan parasitesdifferentiationgene expressionintracellular parasitestranscriptionMicrobiologyQR1-502ENmSphere, Vol 2, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	ApiAP2 apicomplexan parasites differentiation gene expression intracellular parasites transcription Microbiology QR1-502
spellingShingle	ApiAP2 apicomplexan parasites differentiation gene expression intracellular parasites transcription Microbiology QR1-502 Sherri Huang Michael J. Holmes Joshua B. Radke Dong-Pyo Hong Ting-Kai Liu Michael W. White William J. Sullivan <named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development
description	ABSTRACT Toxoplasma gondii is a protozoan parasite of great importance to human and animal health. In the host, this obligate intracellular parasite persists as a tissue cyst that is imperceptible to the immune response and unaffected by current therapies. The tissue cysts facilitate transmission through predation and give rise to chronic cycles of toxoplasmosis in immunocompromised patients. Transcriptional changes accompany conversion of the rapidly replicating tachyzoites into the encysted bradyzoites, and yet the mechanisms underlying these alterations in gene expression are not well defined. Here we show that AP2IX-4 is a nuclear protein exclusively expressed in tachyzoites and bradyzoites undergoing division. Knockout of AP2IX-4 had no discernible effect on tachyzoite replication but resulted in a reduced frequency of tissue cyst formation following alkaline stress induction—a defect that is reversible by complementation. AP2IX-4 has a complex role in regulating bradyzoite gene expression, as the levels of many bradyzoite mRNAs dramatically increased beyond those seen under conditions of normal stress induction in AP2IX-4 knockout parasites exposed to alkaline media. The loss of AP2IX-4 also resulted in a modest virulence defect and reduced cyst burden in chronically infected mice, which was reversed by complementation. These findings illustrate that the transcriptional mechanisms responsible for tissue cyst development operate across the intermediate life cycle from the dividing tachyzoite to the dormant bradyzoite. IMPORTANCE Toxoplasma gondii is a single-celled parasite that persists in its host as a transmissible tissue cyst. How the parasite converts from its replicative form to the bradyzoites housed in tissue cysts is not well understood, but the process clearly involves changes in gene expression. Here we report that parasites lacking a cell cycle-regulated transcription factor called AP2IX-4 display reduced frequencies of tissue cyst formation in culture and in a mouse model of infection. Parasites missing AP2IX-4 lose the ability to regulate bradyzoite genes during tissue cyst development. Expressed in developing bradyzoites still undergoing division, AP2IX-4 may serve as a useful marker in the study of transitional forms of the parasite.
format	article
author	Sherri Huang Michael J. Holmes Joshua B. Radke Dong-Pyo Hong Ting-Kai Liu Michael W. White William J. Sullivan
author_facet	Sherri Huang Michael J. Holmes Joshua B. Radke Dong-Pyo Hong Ting-Kai Liu Michael W. White William J. Sullivan
author_sort	Sherri Huang
title	<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development
title_short	<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development
title_full	<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development
title_fullStr	<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development
title_full_unstemmed	<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development
title_sort	<named-content content-type="genus-species">toxoplasma gondii</named-content> ap2ix-4 regulates gene expression during bradyzoite development
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/45c1ca02eef54ef589b238165f1c8c0e
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<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2IX-4 Regulates Gene Expression during Bradyzoite Development

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