<named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development
ABSTRACT Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects warm-blooded vertebrates, including humans. Asexual reproduction in T. gondii allows it to switch between the rapidly replicating tachyzoite and quiescent bradyzoite life cycle stages. A transient cyclic AMP (...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2016-07-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00755-16 |
| _version_ | 1818843757198442496 |
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| author | Tatsuki Sugi Yan Fen Ma Tadakimi Tomita Fumi Murakoshi Michael S. Eaton Rama Yakubu Bing Han Vincent Tu Kentaro Kato Shin-Ichiro Kawazu Nishith Gupta Elena S. Suvorova Michael W. White Kami Kim Louis M. Weiss |
| author_facet | Tatsuki Sugi Yan Fen Ma Tadakimi Tomita Fumi Murakoshi Michael S. Eaton Rama Yakubu Bing Han Vincent Tu Kentaro Kato Shin-Ichiro Kawazu Nishith Gupta Elena S. Suvorova Michael W. White Kami Kim Louis M. Weiss |
| author_sort | Tatsuki Sugi |
| collection | DOAJ |
| description | ABSTRACT Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects warm-blooded vertebrates, including humans. Asexual reproduction in T. gondii allows it to switch between the rapidly replicating tachyzoite and quiescent bradyzoite life cycle stages. A transient cyclic AMP (cAMP) pulse promotes bradyzoite differentiation, whereas a prolonged elevation of cAMP inhibits this process. We investigated the mechanism(s) by which differential modulation of cAMP exerts a bidirectional effect on parasite differentiation. There are three protein kinase A (PKA) catalytic subunits (TgPKAc1 to -3) expressed in T. gondii. Unlike TgPKAc1 and TgPKAc2, which are conserved in the phylum Apicomplexa, TgPKAc3 appears evolutionarily divergent and specific to coccidian parasites. TgPKAc1 and TgPKAc2 are distributed in the cytomembranes, whereas TgPKAc3 resides in the cytosol. TgPKAc3 was genetically ablated in a type II cyst-forming strain of T. gondii (PruΔku80Δhxgprt) and in a type I strain (RHΔku80Δhxgprt), which typically does not form cysts. The Δpkac3 mutant exhibited slower growth than the parental and complemented strains, which correlated with a higher basal rate of tachyzoite-to-bradyzoite differentiation. 3-Isobutyl-1-methylxanthine (IBMX) treatment, which elevates cAMP levels, maintained wild-type parasites as tachyzoites under bradyzoite induction culture conditions (pH 8.2/low CO2), whereas the Δpkac3 mutant failed to respond to the treatment. This suggests that TgPKAc3 is the factor responsible for the cAMP-dependent tachyzoite maintenance. In addition, the Δpkac3 mutant had a defect in the production of brain cysts in vivo, suggesting that a substrate of TgPKAc3 is probably involved in the persistence of this parasite in the intermediate host animals. IMPORTANCE Toxoplasma gondii is one of the most prevalent eukaryotic parasites in mammals, including humans. Parasites can switch from rapidly replicating tachyzoites responsible for acute infection to slowly replicating bradyzoites that persist as a latent infection. Previous studies have demonstrated that T. gondii cAMP signaling can induce or suppress bradyzoite differentiation, depending on the strength and duration of cAMP signal. Here, we report that TgPKAc3 is responsible for cAMP-dependent tachyzoite maintenance while suppressing differentiation into bradyzoites, revealing one mechanism underlying how this parasite transduces cAMP signals during differentiation. |
| first_indexed | 2024-12-19T05:02:56Z |
| format | Article |
| id | doaj.art-7a6068404b7649e8a47449c1def855c2 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T05:02:56Z |
| publishDate | 2016-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-7a6068404b7649e8a47449c1def855c22022-12-21T20:35:01ZengAmerican Society for MicrobiologymBio2150-75112016-07-017310.1128/mBio.00755-16<named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite DevelopmentTatsuki Sugi0Yan Fen Ma1Tadakimi Tomita2Fumi Murakoshi3Michael S. Eaton4Rama Yakubu5Bing Han6Vincent Tu7Kentaro Kato8Shin-Ichiro Kawazu9Nishith Gupta10Elena S. Suvorova11Michael W. White12Kami Kim13Louis M. Weiss14Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USANational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USANational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanDepartment of Molecular Parasitology, Humboldt University, Berlin, GermanyDepartments of Molecular Medicine and Global Health, University of South Florida, Tampa, Florida, USADepartments of Molecular Medicine and Global Health, University of South Florida, Tampa, Florida, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Pathology, Albert Einstein College of Medicine, Bronx, New York, USAABSTRACT Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects warm-blooded vertebrates, including humans. Asexual reproduction in T. gondii allows it to switch between the rapidly replicating tachyzoite and quiescent bradyzoite life cycle stages. A transient cyclic AMP (cAMP) pulse promotes bradyzoite differentiation, whereas a prolonged elevation of cAMP inhibits this process. We investigated the mechanism(s) by which differential modulation of cAMP exerts a bidirectional effect on parasite differentiation. There are three protein kinase A (PKA) catalytic subunits (TgPKAc1 to -3) expressed in T. gondii. Unlike TgPKAc1 and TgPKAc2, which are conserved in the phylum Apicomplexa, TgPKAc3 appears evolutionarily divergent and specific to coccidian parasites. TgPKAc1 and TgPKAc2 are distributed in the cytomembranes, whereas TgPKAc3 resides in the cytosol. TgPKAc3 was genetically ablated in a type II cyst-forming strain of T. gondii (PruΔku80Δhxgprt) and in a type I strain (RHΔku80Δhxgprt), which typically does not form cysts. The Δpkac3 mutant exhibited slower growth than the parental and complemented strains, which correlated with a higher basal rate of tachyzoite-to-bradyzoite differentiation. 3-Isobutyl-1-methylxanthine (IBMX) treatment, which elevates cAMP levels, maintained wild-type parasites as tachyzoites under bradyzoite induction culture conditions (pH 8.2/low CO2), whereas the Δpkac3 mutant failed to respond to the treatment. This suggests that TgPKAc3 is the factor responsible for the cAMP-dependent tachyzoite maintenance. In addition, the Δpkac3 mutant had a defect in the production of brain cysts in vivo, suggesting that a substrate of TgPKAc3 is probably involved in the persistence of this parasite in the intermediate host animals. IMPORTANCE Toxoplasma gondii is one of the most prevalent eukaryotic parasites in mammals, including humans. Parasites can switch from rapidly replicating tachyzoites responsible for acute infection to slowly replicating bradyzoites that persist as a latent infection. Previous studies have demonstrated that T. gondii cAMP signaling can induce or suppress bradyzoite differentiation, depending on the strength and duration of cAMP signal. Here, we report that TgPKAc3 is responsible for cAMP-dependent tachyzoite maintenance while suppressing differentiation into bradyzoites, revealing one mechanism underlying how this parasite transduces cAMP signals during differentiation.https://journals.asm.org/doi/10.1128/mBio.00755-16 |
| spellingShingle | Tatsuki Sugi Yan Fen Ma Tadakimi Tomita Fumi Murakoshi Michael S. Eaton Rama Yakubu Bing Han Vincent Tu Kentaro Kato Shin-Ichiro Kawazu Nishith Gupta Elena S. Suvorova Michael W. White Kami Kim Louis M. Weiss <named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development mBio |
| title | <named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development |
| title_full | <named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development |
| title_fullStr | <named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development |
| title_full_unstemmed | <named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development |
| title_short | <named-content content-type="genus-species">Toxoplasma gondii</named-content> Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development |
| title_sort | named content content type genus species toxoplasma gondii named content cyclic amp dependent protein kinase subunit 3 is involved in the switch from tachyzoite to bradyzoite development |
| url | https://journals.asm.org/doi/10.1128/mBio.00755-16 |
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