{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T09:56:26Z","timestamp":1789898186986,"version":"4.0.1"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2016,5,31]],"date-time":"2016-05-31T00:00:00Z","timestamp":1464652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,7,6]],"date-time":"2016-07-06T00:00:00Z","timestamp":1467763200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2016,7,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>\n            is an obligate intracellular apicomplexan parasite that infects warm-blooded vertebrates, including humans. Asexual reproduction in\n            <jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>\n            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 (\n            <jats:italic>Tg<\/jats:italic>\n            PKAc1 to -3) expressed in\n            <jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>\n            . Unlike\n            <jats:italic>Tg<\/jats:italic>\n            PKAc1 and\n            <jats:italic>Tg<\/jats:italic>\n            PKAc2, which are conserved in the phylum Apicomplexa,\n            <jats:italic>Tg<\/jats:italic>\n            PKAc3 appears evolutionarily divergent and specific to coccidian parasites.\n            <jats:italic>Tg<\/jats:italic>\n            PKAc1 and\n            <jats:italic>Tg<\/jats:italic>\n            PKAc2 are distributed in the cytomembranes, whereas\n            <jats:italic>Tg<\/jats:italic>\n            PKAc3 resides in the cytosol.\n            <jats:italic>Tg<\/jats:italic>\n            PKAc3 was genetically ablated in a type II cyst-forming strain of\n            <jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>\n            (Pru\n            <jats:italic>\u0394ku80\u0394hxgprt<\/jats:italic>\n            ) and in a type I strain (RH\n            <jats:italic>\u0394ku80\u0394hxgprt<\/jats:italic>\n            ), which typically does not form cysts. The \u0394\n            <jats:italic>pkac3<\/jats:italic>\n            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\u00a08.2\/low CO\n            <jats:sub>2<\/jats:sub>\n            ), whereas the \u0394\n            <jats:italic>pkac3<\/jats:italic>\n            mutant failed to respond to the treatment. This suggests that\n            <jats:italic>Tg<\/jats:italic>\n            PKAc3 is the factor responsible for the cAMP-dependent tachyzoite maintenance. In addition, the \u0394\n            <jats:italic>pkac3<\/jats:italic>\n            mutant had a defect in the production of brain cysts\n            <jats:italic>in vivo<\/jats:italic>\n            , suggesting that a substrate of\n            <jats:italic>Tg<\/jats:italic>\n            PKAc3 is probably involved in the persistence of this parasite in the intermediate host animals.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            <jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>\n            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\n            <jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>\n            cAMP signaling can induce or suppress bradyzoite differentiation, depending on the strength and duration of cAMP signal. Here, we report that\n            <jats:italic>Tg<\/jats:italic>\n            PKAc3 is responsible for cAMP-dependent tachyzoite maintenance while suppressing differentiation into bradyzoites, revealing one mechanism underlying how this parasite transduces cAMP signals during differentiation.\n          <\/jats:p>","DOI":"10.1128\/mbio.00755-16","type":"journal-article","created":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T01:48:34Z","timestamp":1464745714000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":66,"title":["Toxoplasma gondii Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development"],"prefix":"10.1128","volume":"7","author":[{"given":"Tatsuki","family":"Sugi","sequence":"first","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"name":"National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Fen","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadakimi","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumi","family":"Murakoshi","sequence":"additional","affiliation":[{"name":"National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Eaton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Yakubu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Kato","sequence":"additional","affiliation":[{"name":"National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ichiro","family":"Kawazu","sequence":"additional","affiliation":[{"name":"National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishith","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology, Humboldt University, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena S.","family":"Suvorova","sequence":"additional","affiliation":[{"name":"Departments of Molecular Medicine and Global Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"White","sequence":"additional","affiliation":[{"name":"Departments of Molecular Medicine and Global Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kami","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"name":"Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"name":"Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2009.04.003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1550-7408.1976.tb03836.x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.05486-11"},{"key":"e_1_3_2_5_2","volume-title":"Toxoplasma gondii. The model apicomplexan\u2014perspectives and methods","author":"Weiss L","year":"2014","unstructured":"Weiss L, Kim K. 2014. Toxoplasma gondii. The model apicomplexan\u2014perspectives and methods, 2nd ed. Academic Press (Elsevier Inc.), London, United Kingdom.","edition":"2"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1039\/b800520f"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.1.148-153.2001"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.465583"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104607"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13783"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.100113397"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022492"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2005.08.014"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000941"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-1225-x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00297-10"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01155-15"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(03)00198-1"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02094-15"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.10.4838-4844.1998"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.12.8038"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12121"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003830"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4585"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300059110"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.06167-11"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1189"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mst197"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msn067"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00357-08"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2008.01.001"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003823"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2014.12.001"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1078\/0171-9335-00214"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00351-09"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2010.01514.x"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00755-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00755-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T02:01:45Z","timestamp":1646704905000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.00755-16"}},"subtitle":[],"editor":[{"given":"L. David","family":"Sibley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,7,6]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2016,7,6]]}},"alternative-id":["10.1128\/mBio.00755-16"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00755-16","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,6]]},"assertion":[{"value":"2016-04-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00755-16"}}