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The study of transcriptional signatures to investigate host immune responses in infectious disease

Blankley, SFK; (2015) The study of transcriptional signatures to investigate host immune responses in infectious disease. Doctoral thesis , UCL (University College London).

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Abstract

Tuberculosis (TB) remains the leading cause of infectious death worldwide, not all individuals who are infected with Mycobacterium tuberculosis (Mtb) will develop disease, approximately 90 per cent remain in an asymptomatic state termed latent infection. The initial infection with Mtb usually occurs in the lungs following inhalation and the majority of those with active TB develop it in the lungs. The host immune factors which lead to the establishment and maintenance of a latent state or the host immune factors which permit Mtb to escape the lungs to cause extra-pulmonary infection are yet to be fully understood. Modern whole genome expression technology can capture the expression level of over 40,000 transcripts simultaneously; using bioinformatic analytical approaches it been possible to profile the transcriptional response of whole blood in pulmonary TB, identifying enrichment for interferon signalling and an under-appreciated potential role of type I IFN in pathogenesis of pulmonary TB. Using whole genome expression technology and a range of bioinformatic tools I sought to identify differentially expressed genes associated with infection with Mtb. I established the utility of an in vitro whole blood stimulation system and characterised the temporal transcriptional response following stimulation with pattern-recognition receptor ligands and the mycobacterial peptide Ag85B. I undertook a meta-analysis of publicly available microarray data and identified a 380 gene meta-signature which revealed enrichment for innate immune functions such as complement, interferon signalling, inflammasome and pattern-recognition receptor signalling. I tested this meta-signature in a novel dataset including both pulmonary and extra-pulmonary TB patients and showed that gene expression of TB patients varies depending on site of disease and symptom status of the individual. This study has provided new insights into the host immune response in TB and the findings will contribute to the ongoing search for robust biomarkers and factors involved in TB pathogenesis.

Type: Thesis (Doctoral)
Title: The study of transcriptional signatures to investigate host immune responses in infectious disease
Event: UCL (University College London)
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1471015
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