AP2IX-4, a cell cycle regulated nuclear factor, modulates gene expression during bradyzoite development in toxoplasma gondii

dc.contributor.advisorArrizabalaga, Gustavo
dc.contributor.authorHuang, Sherri Y.
dc.contributor.otherSullivan, William J., Jr.
dc.contributor.otherLu, Tao
dc.contributor.otherTakagi, Yuichiro
dc.contributor.otherZhang, Jian-Ting
dc.date.accessioned2017-05-15T18:28:13Z
dc.date.available2017-05-15T18:28:13Z
dc.date.issued2017-01-10
dc.degree.date2017en_US
dc.degree.disciplineDepartment of Pharmacology & Toxicology
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractToxoplasma gondii is a ubiquitous, protozoan parasite contributing significantly to global human and animal health. In the host, this obligate intracellular parasite converts into a latent tissue cyst form known as the bradyzoite, which is impervious to the immune response. The tissue cysts facilitate wide-spread transmission through the food chain and give rise to chronic toxoplasmosis in immune compromised patients. In addition, they may reactivate into replicating tachyzoites which cause tissue damage and disseminated disease. Current available drugs do not appear to have appreciable activity against latent bradyzoites. Therefore, a better understanding of the molecular mechanisms that drive interconversion between tachyzoite and bradyzoite forms is required to manage transmission and pathogenesis of Toxoplasma. Conversion to the bradyzoite is accompanied by an altered transcriptome, but the molecular players directing this process are largely uncharacterized. Studies of stage-specific promoters revealed that conventional cis-acting mechanisms operate to regulate developmental gene expression during tissue cyst formation. The major class of transcription factor likely to work through these cis-regulatory elements appears to be related to the Apetala-2 (AP2) family in plants. The Toxoplasma genome contains nearly 70 proteins harboring at least one predicted AP2 domain, but to date only three of these T. gondii AP2 proteins have been linked to bradyzoite development. We show that the putative T. gondii transcription factor, AP2IX-4, is localized to the parasite nucleus and exclusively expressed in tachyzoites and bradyzoites undergoing division. Knockout of AP2IX-4 had negligible effect on tachyzoite replication, but resulted in a reduced frequency of bradyzoite cysts in response to alkaline stress induction – a defect that is reversible by complementation. Microarray analyses revealed an enhanced activation of bradyzoite-associated genes in the AP2IX-4 knockout during alkaline conditions. In mice, the loss of AP2IX-4 resulted in a modest virulence defect and reduced brain cyst burden. Complementation of the AP2IX-4 knockout restored cyst counts to wild-type levels. These findings illustrate the complex role of AP2IX-4 in bradyzoite development and that certain transcriptional mechanisms responsible for tissue cyst development operate across parasite division.en_US
dc.identifier.doi10.7912/C2R01N
dc.identifier.urihttps://hdl.handle.net/1805/12538
dc.identifier.urihttp://dx.doi.org/10.7912/C2/322
dc.language.isoen_USen_US
dc.subjectApiAP2en_US
dc.subjectToxoplasma gondiien_US
dc.subjectApicomplexan parasitesen_US
dc.subjectGene expressionen_US
dc.subjectParasite differentiationen_US
dc.subjectTranscriptionen_US
dc.titleAP2IX-4, a cell cycle regulated nuclear factor, modulates gene expression during bradyzoite development in toxoplasma gondiien_US
dc.typeThesis
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