Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.794174
Title: Host-pathogen interactions of Toxoplasma gondii : catecholamine biosynthesis and epigenetic changes in neuronal cells during infection
Author: Badya, Norhidayah Binti
ISNI:       0000 0004 8498 7219
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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Abstract:
The apicomplexan parasite Toxoplasma gondii establishes chronic infection as intracellular cysts inside the brain and muscle tissue; able to infect virtually all mammals including humans. Modulation of host behaviour in rodents has been associated with promoting transmission and lifelong persistence. The neurophysiological changes associated with infection remain unclear, however catecholamine dysregulation has been observed in infected neurotransmitter-expressing cells and brain tissue. The experiments within this thesis examine the mechanisms whereby the parasite downregulates the expression of dopamine ß-hydroxylase (DBH), the key enzyme required for converting dopamine into norepinephrine (NE), following prior studies showing NE suppression with infection. My experiments identified a long non-coding RNA (lncRNA) in infected cells that is in the antisense orientation to the DBH gene. This lncRNA may be associated with DNA methyltransferase 3 alpha (DNMT3a)-binding in the DBH promoter region which was elevated from day one post-infection rising to three- fold on day two. Time-dependent chromatin changes in the DBH promoter occurred with increased DNA methylation and dimethylation of H3K9 (H3K9me2) histone modifications, supporting previous findings of downregulation of the DBH gene. The minimal changes in chromatin observed in this study are consistent with the levels of NE and DBH suppression observed in the neural PC12 cells that were used. The presence of lncRNA in the DBH gene promoter in T. gondii-infected cells is proposed to play a role in alterations observed in host gene expression. The data in this thesis highlight a new form of epigenetic control of the host cell during parasitic infection. Model mechanisms of how the detected lncRNA control gene expression in T. gondii-infected neural cells are proposed.
Supervisor: McConkey, Glenn A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.794174  DOI: Not available
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