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To facilitate the acute phase of the infection,<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>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<jats:italic>ROPK<\/jats:italic>gene loci encoding 31 unique ROPK proteins of type II<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>and show that numerous ROPK proteins influence the development of chronic infection. Cyst burdens were increased in the \u0394<jats:italic>rop16<\/jats:italic>knockout strain or moderately reduced in 11<jats:italic>ROPK<\/jats:italic>knockout strains. In contrast, deletion of<jats:italic>ROP5<\/jats:italic>,<jats:italic>ROP17<\/jats:italic>,<jats:italic>ROP18<\/jats:italic>,<jats:italic>ROP35<\/jats:italic>, or<jats:italic>ROP38<\/jats:italic>\/<jats:italic>29<\/jats:italic>\/<jats:italic>19<\/jats:italic>(<jats:italic>ROP38<\/jats:italic>,<jats:italic>ROP29<\/jats:italic>, and<jats:italic>ROP19<\/jats:italic>) severely reduced cyst burdens. \u0394<jats:italic>rop5<\/jats:italic>and \u0394<jats:italic>rop18<\/jats:italic>knockout strains were less resistant to host immunity-related GTPases (IRGs) and exhibited &gt;100-fold-reduced virulence. ROP18 kinase activity and association with the parasitophorous vacuole membrane were necessary for resistance to host IRGs. The \u0394<jats:italic>rop17<\/jats:italic>strain exhibited a &gt;12-fold defect in virulence; however, virulence was not affected in the \u0394<jats:italic>rop35<\/jats:italic>or \u0394<jats:italic>rop38<\/jats:italic>\/<jats:italic>29<\/jats:italic>\/<jats:italic>19<\/jats:italic>strain. Resistance to host IRGs was not affected in the \u0394<jats:italic>rop17<\/jats:italic>, \u0394<jats:italic>rop35<\/jats:italic>, or \u0394<jats:italic>rop38<\/jats:italic>\/<jats:italic>29<\/jats:italic>\/<jats:italic>19<\/jats:italic>strain. Collectively, these findings provide the first definitive evidence that the type II<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>ROPK proteome functions as virulence factors and facilitates additional mechanisms of host manipulation that are essential for chronic infection and transmission of<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Reactivation of chronic<jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>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.<\/jats:p>","DOI":"10.1128\/mbio.00193-16","type":"journal-article","created":{"date-parts":[[2016,5,11]],"date-time":"2016-05-11T02:22:35Z","timestamp":1462933355000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":85,"title":["The Toxoplasma gondii Rhoptry Kinome Is Essential for Chronic Infection"],"prefix":"10.1128","volume":"7","author":[{"given":"Barbara A.","family":"Fox","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah M.","family":"Rommereim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah B.","family":"Guevara","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Falla","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miryam Andrea","family":"Hortua Triana","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Bzik","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"1","volume-title":"Toxoplasma gondii: the model apicomplexan parasite: perspectives and methods","author":"Dubey JP","year":"2007","unstructured":"Dubey JP. 2007. 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