The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection

ABSTRACT Ingestion of the obligate intracellular protozoan parasite Toxoplasma gondii causes an acute infection that leads to chronic infection of the host. To facilitate the acute phase of the infection, T. gondii manipulates the host response by secreting rhoptry organelle proteins (ROPs) into...

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Autores principales:	Barbara A. Fox, Leah M. Rommereim, Rebekah B. Guevara, Alejandra Falla, Miryam Andrea Hortua Triana, Yanbo Sun, David J. Bzik
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0ec0ff4f48d74421a21043f39df20e32
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spelling	oai:doaj.org-article:0ec0ff4f48d74421a21043f39df20e322021-11-15T15:50:16ZThe <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection10.1128/mBio.00193-162150-7511https://doaj.org/article/0ec0ff4f48d74421a21043f39df20e322016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00193-16https://doaj.org/toc/2150-7511ABSTRACT Ingestion of the obligate intracellular protozoan parasite Toxoplasma gondii causes an acute infection that leads to chronic infection of the host. To facilitate the acute phase of the infection, T. gondii manipulates the host response by secreting rhoptry organelle proteins (ROPs) into host cells during its invasion. A few key ROP proteins with signatures of kinases or pseudokinases (ROPKs) act as virulence factors that enhance parasite survival against host gamma interferon-stimulated innate immunity. However, the roles of these and other ROPK proteins in establishing chronic infection have not been tested. Here, we deleted 26 ROPK gene loci encoding 31 unique ROPK proteins of type II T. gondii and show that numerous ROPK proteins influence the development of chronic infection. Cyst burdens were increased in the Δrop16 knockout strain or moderately reduced in 11 ROPK knockout strains. In contrast, deletion of ROP5, ROP17, ROP18, ROP35, or ROP38/29/19 (ROP38, ROP29, and ROP19) severely reduced cyst burdens. Δrop5 and Δrop18 knockout strains were less resistant to host immunity-related GTPases (IRGs) and exhibited >100-fold-reduced virulence. ROP18 kinase activity and association with the parasitophorous vacuole membrane were necessary for resistance to host IRGs. The Δrop17 strain exhibited a >12-fold defect in virulence; however, virulence was not affected in the Δrop35 or Δrop38/29/19 strain. Resistance to host IRGs was not affected in the Δrop17, Δrop35, or Δrop38/29/19 strain. Collectively, these findings provide the first definitive evidence that the type II T. gondii ROPK proteome functions as virulence factors and facilitates additional mechanisms of host manipulation that are essential for chronic infection and transmission of T. gondii. IMPORTANCE Reactivation of chronic Toxoplasma gondii infection in individuals with weakened immune systems causes severe toxoplasmosis. Existing treatments for toxoplasmosis are complicated by adverse reactions to chemotherapy. Understanding key parasite molecules required for chronic infection provides new insights into potential mechanisms that can interrupt parasite survival or persistence in the host. This study reveals that key secreted rhoptry molecules are used by the parasite to establish chronic infection of the host. Certain rhoptry proteins were found to be critical virulence factors that resist innate immunity, while other rhoptry proteins were found to influence chronic infection without affecting virulence. This study reveals that rhoptry proteins utilize multiple mechanisms of host manipulation to establish chronic infection of the host. Targeted disruption of parasite rhoptry proteins involved in these biological processes opens new avenues to interfere with chronic infection with the goal to either eliminate chronic infection or to prevent recrudescent infections.Barbara A. FoxLeah M. RommereimRebekah B. GuevaraAlejandra FallaMiryam Andrea Hortua TrianaYanbo SunDavid J. BzikAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Barbara A. Fox Leah M. Rommereim Rebekah B. Guevara Alejandra Falla Miryam Andrea Hortua Triana Yanbo Sun David J. Bzik The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection
description	ABSTRACT Ingestion of the obligate intracellular protozoan parasite Toxoplasma gondii causes an acute infection that leads to chronic infection of the host. To facilitate the acute phase of the infection, T. gondii manipulates the host response by secreting rhoptry organelle proteins (ROPs) into host cells during its invasion. A few key ROP proteins with signatures of kinases or pseudokinases (ROPKs) act as virulence factors that enhance parasite survival against host gamma interferon-stimulated innate immunity. However, the roles of these and other ROPK proteins in establishing chronic infection have not been tested. Here, we deleted 26 ROPK gene loci encoding 31 unique ROPK proteins of type II T. gondii and show that numerous ROPK proteins influence the development of chronic infection. Cyst burdens were increased in the Δrop16 knockout strain or moderately reduced in 11 ROPK knockout strains. In contrast, deletion of ROP5, ROP17, ROP18, ROP35, or ROP38/29/19 (ROP38, ROP29, and ROP19) severely reduced cyst burdens. Δrop5 and Δrop18 knockout strains were less resistant to host immunity-related GTPases (IRGs) and exhibited >100-fold-reduced virulence. ROP18 kinase activity and association with the parasitophorous vacuole membrane were necessary for resistance to host IRGs. The Δrop17 strain exhibited a >12-fold defect in virulence; however, virulence was not affected in the Δrop35 or Δrop38/29/19 strain. Resistance to host IRGs was not affected in the Δrop17, Δrop35, or Δrop38/29/19 strain. Collectively, these findings provide the first definitive evidence that the type II T. gondii ROPK proteome functions as virulence factors and facilitates additional mechanisms of host manipulation that are essential for chronic infection and transmission of T. gondii. IMPORTANCE Reactivation of chronic Toxoplasma gondii infection in individuals with weakened immune systems causes severe toxoplasmosis. Existing treatments for toxoplasmosis are complicated by adverse reactions to chemotherapy. Understanding key parasite molecules required for chronic infection provides new insights into potential mechanisms that can interrupt parasite survival or persistence in the host. This study reveals that key secreted rhoptry molecules are used by the parasite to establish chronic infection of the host. Certain rhoptry proteins were found to be critical virulence factors that resist innate immunity, while other rhoptry proteins were found to influence chronic infection without affecting virulence. This study reveals that rhoptry proteins utilize multiple mechanisms of host manipulation to establish chronic infection of the host. Targeted disruption of parasite rhoptry proteins involved in these biological processes opens new avenues to interfere with chronic infection with the goal to either eliminate chronic infection or to prevent recrudescent infections.
format	article
author	Barbara A. Fox Leah M. Rommereim Rebekah B. Guevara Alejandra Falla Miryam Andrea Hortua Triana Yanbo Sun David J. Bzik
author_facet	Barbara A. Fox Leah M. Rommereim Rebekah B. Guevara Alejandra Falla Miryam Andrea Hortua Triana Yanbo Sun David J. Bzik
author_sort	Barbara A. Fox
title	The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection
title_short	The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection
title_full	The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection
title_fullStr	The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection
title_full_unstemmed	The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection
title_sort	<named-content content-type="genus-species">toxoplasma gondii</named-content> rhoptry kinome is essential for chronic infection
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/0ec0ff4f48d74421a21043f39df20e32
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The <named-content content-type="genus-species">Toxoplasma gondii</named-content> Rhoptry Kinome Is Essential for Chronic Infection

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