The transciptomic landscape of HIV-TB

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dc.contributor.advisorMulder, Nicolaen_ZA
dc.contributor.advisorWilkinson, Robert Jen_ZA
dc.contributor.advisorMayosi, Bongani Men_ZA
dc.contributor.authorDeffur, Arminen_ZA
dc.date.accessioned2014-07-29T09:03:07Z
dc.date.available2014-07-29T09:03:07Z
dc.date.issued2013en_ZA
dc.descriptionIncludes abstract.
dc.descriptionIncludes bibliographical references.
dc.description.abstractThe thesis consists of four main parts. In Part 1 of this thesis I provide a broad overview of HIVTB with an emphasis on systems approaches followed by an overview of a systems-level study aiming at addressing hypotheses relating to transcriptional differences in active tuberculosis and HIV-1 infection, measured in blood and the site of disease in tuberculous pericarditis. The final chapter in this part describes the methods used to generate and analyse the systems-level data, with emphasis on microarray data generation and analysis. Part 2 first presents analysis of transcriptional data generated by RT-PCR at the site of disease compared to blood in study subjects with tuberculous pericarditis, with results showing clear evidence of transcriptional differences between compartments. A Technical Results chapter then provides an overview of the microarray data, and an analytic paradigm based on sample embedding in high-dimensional phenotype space is developed. I then assess the overall quality of the dataset and exclude large-scale systematic bias, while comparison of the IMPI-MA data to exiting TBtranscriptomic data shows a close match. Part 2 concludes with a description of a comprehensive analytic framework developed for the IMPI-MA data. Part 3 presents the results of the analytic pipeline as applied to the transcriptional response in blood to active tuberculosis in an HIV-1 uninfected population. A signature of active tuberculosis is described, and deconvolution analysis finds significant NK cell activation in active tuberculosis. Cell-type specific differential expression identifies CD4 T cells, NK cells and neutrophils as the most likely contributors to the overall “signature” of active tuberculosis. Weighted gene co-expression network analysis reveals multiple modules, whose expression is shown to be differentially regulated based on disease category. Part 4 summarises the results of analysing contrasts in three main contexts: tuberculosis, HIV-1 infection and compartment. Two novel results are presented: Firstly, NK cells are shown to be functionally downregulated at the site of disease, suggesting a possible defence mechanism by M. tuberculosis, and secondly, large-scale metabolic pathway dysregulation at the site of disease, possibly favouring M. tuberculosis, is demonstrated. Part 5 concludes the thesis with a summary and outlines future work.en_ZA
dc.identifier.apacitationDeffur, A. (2013). <i>The transciptomic landscape of HIV-TB</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/3377en_ZA
dc.identifier.chicagocitationDeffur, Armin. <i>"The transciptomic landscape of HIV-TB."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2013. http://hdl.handle.net/11427/3377en_ZA
dc.identifier.citationDeffur, A. 2013. The transciptomic landscape of HIV-TB. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Deffur, Armin AB - The thesis consists of four main parts. In Part 1 of this thesis I provide a broad overview of HIVTB with an emphasis on systems approaches followed by an overview of a systems-level study aiming at addressing hypotheses relating to transcriptional differences in active tuberculosis and HIV-1 infection, measured in blood and the site of disease in tuberculous pericarditis. The final chapter in this part describes the methods used to generate and analyse the systems-level data, with emphasis on microarray data generation and analysis. Part 2 first presents analysis of transcriptional data generated by RT-PCR at the site of disease compared to blood in study subjects with tuberculous pericarditis, with results showing clear evidence of transcriptional differences between compartments. A Technical Results chapter then provides an overview of the microarray data, and an analytic paradigm based on sample embedding in high-dimensional phenotype space is developed. I then assess the overall quality of the dataset and exclude large-scale systematic bias, while comparison of the IMPI-MA data to exiting TBtranscriptomic data shows a close match. Part 2 concludes with a description of a comprehensive analytic framework developed for the IMPI-MA data. Part 3 presents the results of the analytic pipeline as applied to the transcriptional response in blood to active tuberculosis in an HIV-1 uninfected population. A signature of active tuberculosis is described, and deconvolution analysis finds significant NK cell activation in active tuberculosis. Cell-type specific differential expression identifies CD4 T cells, NK cells and neutrophils as the most likely contributors to the overall “signature” of active tuberculosis. Weighted gene co-expression network analysis reveals multiple modules, whose expression is shown to be differentially regulated based on disease category. Part 4 summarises the results of analysing contrasts in three main contexts: tuberculosis, HIV-1 infection and compartment. Two novel results are presented: Firstly, NK cells are shown to be functionally downregulated at the site of disease, suggesting a possible defence mechanism by M. tuberculosis, and secondly, large-scale metabolic pathway dysregulation at the site of disease, possibly favouring M. tuberculosis, is demonstrated. Part 5 concludes the thesis with a summary and outlines future work. DA - 2013 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - The transciptomic landscape of HIV-TB TI - The transciptomic landscape of HIV-TB UR - http://hdl.handle.net/11427/3377 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/3377
dc.identifier.vancouvercitationDeffur A. The transciptomic landscape of HIV-TB. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2013 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/3377en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherMedicineen_ZA
dc.titleThe transciptomic landscape of HIV-TBen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePh Den_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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