Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance

ABSTRACT Toxoplasma gondii is a ubiquitous pathogen that can cause encephalitis, congenital defects, and ocular disease. T. gondii has also been implicated as a risk factor for mental illness in humans. The parasite persists in the brain as slow-growing bradyzoites contained within intracellular cys...

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Autores principales:	Geetha Kannan, Manlio Di Cristina, Aric J. Schultz, My-Hang Huynh, Fengrong Wang, Tracey L. Schultz, Matteo Lunghi, Isabelle Coppens, Vern B. Carruthers
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Toxoplasma gondii autophagy persistence proteolysis transporters Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ae12df682df347df9a095dba059bb18f
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spelling	oai:doaj.org-article:ae12df682df347df9a095dba059bb18f2021-11-15T16:22:11ZRole of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance10.1128/mBio.01324-192150-7511https://doaj.org/article/ae12df682df347df9a095dba059bb18f2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01324-19https://doaj.org/toc/2150-7511ABSTRACT Toxoplasma gondii is a ubiquitous pathogen that can cause encephalitis, congenital defects, and ocular disease. T. gondii has also been implicated as a risk factor for mental illness in humans. The parasite persists in the brain as slow-growing bradyzoites contained within intracellular cysts. No treatments exist to eliminate this form of parasite. Although proteolytic degradation within the parasite lysosome-like vacuolar compartment (VAC) is critical for bradyzoite viability, whether other aspects of the VAC are important for parasite persistence remains unknown. An ortholog of Plasmodium falciparum chloroquine resistance transporter (CRT), TgCRT, has previously been identified in T. gondii. To interrogate the function of TgCRT in chronic-stage bradyzoites and its role in persistence, we knocked out TgCRT in a cystogenic strain and assessed VAC size, VAC digestion of host-derived proteins and parasite autophagosomes, and the viability of in vitro and in vivo bradyzoites. We found that whereas parasites deficient in TgCRT exhibit normal digestion within the VAC, they display a markedly distended VAC and their viability is compromised both in vitro and in vivo. Interestingly, impairing VAC proteolysis in TgCRT-deficient bradyzoites restored VAC size, consistent with a role for TgCRT as a transporter of products of digestion from the VAC. In conjunction with earlier studies, our current findings suggest a functional link between TgCRT and VAC proteolysis. This study provides further evidence of a crucial role for the VAC in bradyzoite persistence and a new potential VAC target to abate chronic Toxoplasma infection. IMPORTANCE Individuals chronically infected with the intracellular parasite Toxoplasma gondii are at risk of experiencing reactivated disease that can result in progressive loss of vision. No effective treatments exist for chronic toxoplasmosis due in part to a poor understanding of the biology underlying chronic infection and a lack of well-validated potential targets. We show here that a T. gondii transporter is functionally linked to protein digestion within the parasite lysosome-like organelle and that this transporter is necessary to sustain chronic infection in culture and in experimentally infected mice. Ablating the transporter results in severe bloating of the lysosome-like organelle. Together with earlier work, this study suggests the parasite’s lysosome-like organelle is vital for parasite survival, thus rendering it a potential target for diminishing infection and reducing the risk of reactivated disease.Geetha KannanManlio Di CristinaAric J. SchultzMy-Hang HuynhFengrong WangTracey L. SchultzMatteo LunghiIsabelle CoppensVern B. CarruthersAmerican Society for MicrobiologyarticleToxoplasma gondiiautophagypersistenceproteolysistransportersMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma gondii autophagy persistence proteolysis transporters Microbiology QR1-502
spellingShingle	Toxoplasma gondii autophagy persistence proteolysis transporters Microbiology QR1-502 Geetha Kannan Manlio Di Cristina Aric J. Schultz My-Hang Huynh Fengrong Wang Tracey L. Schultz Matteo Lunghi Isabelle Coppens Vern B. Carruthers Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance
description	ABSTRACT Toxoplasma gondii is a ubiquitous pathogen that can cause encephalitis, congenital defects, and ocular disease. T. gondii has also been implicated as a risk factor for mental illness in humans. The parasite persists in the brain as slow-growing bradyzoites contained within intracellular cysts. No treatments exist to eliminate this form of parasite. Although proteolytic degradation within the parasite lysosome-like vacuolar compartment (VAC) is critical for bradyzoite viability, whether other aspects of the VAC are important for parasite persistence remains unknown. An ortholog of Plasmodium falciparum chloroquine resistance transporter (CRT), TgCRT, has previously been identified in T. gondii. To interrogate the function of TgCRT in chronic-stage bradyzoites and its role in persistence, we knocked out TgCRT in a cystogenic strain and assessed VAC size, VAC digestion of host-derived proteins and parasite autophagosomes, and the viability of in vitro and in vivo bradyzoites. We found that whereas parasites deficient in TgCRT exhibit normal digestion within the VAC, they display a markedly distended VAC and their viability is compromised both in vitro and in vivo. Interestingly, impairing VAC proteolysis in TgCRT-deficient bradyzoites restored VAC size, consistent with a role for TgCRT as a transporter of products of digestion from the VAC. In conjunction with earlier studies, our current findings suggest a functional link between TgCRT and VAC proteolysis. This study provides further evidence of a crucial role for the VAC in bradyzoite persistence and a new potential VAC target to abate chronic Toxoplasma infection. IMPORTANCE Individuals chronically infected with the intracellular parasite Toxoplasma gondii are at risk of experiencing reactivated disease that can result in progressive loss of vision. No effective treatments exist for chronic toxoplasmosis due in part to a poor understanding of the biology underlying chronic infection and a lack of well-validated potential targets. We show here that a T. gondii transporter is functionally linked to protein digestion within the parasite lysosome-like organelle and that this transporter is necessary to sustain chronic infection in culture and in experimentally infected mice. Ablating the transporter results in severe bloating of the lysosome-like organelle. Together with earlier work, this study suggests the parasite’s lysosome-like organelle is vital for parasite survival, thus rendering it a potential target for diminishing infection and reducing the risk of reactivated disease.
format	article
author	Geetha Kannan Manlio Di Cristina Aric J. Schultz My-Hang Huynh Fengrong Wang Tracey L. Schultz Matteo Lunghi Isabelle Coppens Vern B. Carruthers
author_facet	Geetha Kannan Manlio Di Cristina Aric J. Schultz My-Hang Huynh Fengrong Wang Tracey L. Schultz Matteo Lunghi Isabelle Coppens Vern B. Carruthers
author_sort	Geetha Kannan
title	Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance
title_short	Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance
title_full	Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance
title_fullStr	Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance
title_full_unstemmed	Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance
title_sort	role of <italic toggle="yes">toxoplasma gondii</italic> chloroquine resistance transporter in bradyzoite viability and digestive vacuole maintenance
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ae12df682df347df9a095dba059bb18f
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Role of <italic toggle="yes">Toxoplasma gondii</italic> Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance

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