Host serum protein biomarkers of tuberculosis in sub-Saharan Africa

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Title: Host serum protein biomarkers of tuberculosis in sub-Saharan Africa
Authors: Morris, Thomas
Item Type: Thesis or dissertation
Abstract: Rapid, accurate, affordable, user-friendly and robust diagnostic tests are needed for use in sub-Saharan Africa, where the incidence and case fatality rates of TB are highest. Pathogen detection is such settings is challenging, owing to low abundance in sputum, and the associated need for laboratory-based assays. An alternative to pathogen detection are host-derived biomarkers, from which accurate diagnostic biosignatures can been derived. Of these, host serum proteins are a favourable option owing to their large diversity and abundance, range of clinical sources, response to pathological processes and amenability to immunocapture, including by multiplexed lateral flow immunoassay. In this thesis, I evaluated two approaches to discovering immunocapture-based serum protein diagnostic signatures for TB in cohorts recruited from Malawi and South Africa, primarily from secondary care. The first is to re-test 22 proteins from which a 7-protein signature was recently discovered in a cohort recruited from primary care in Africa. This signature showed potential for use as a screening test in this setting. In our study, a 9-protein signature is discovered that may perform in a similar manner in secondary care. We also studied the levels of a subset of these 22 proteins in a smaller paediatric cohort before and after TB treatment. The second approach was to evaluate the translatability of serum protein biomarkers that were discovered using a mass spectrometry-based platform in our cohort to immunocapture. Results on three such proteins are presented, each with differing but informative outcomes. Patients recruited to our studies were characterised with regards to demographic and clinical variables. In the final part of the thesis, I explore associations between serum protein levels in TB and these variables in order to gain further insight into the biology of TB. Novel associations were discovered with age, body mass index, smear grade and CD4+ count.
Content Version: Open Access
Issue Date: Dec-2019
Date Awarded: Jun-2020
URI: http://hdl.handle.net/10044/1/97985
DOI: https://doi.org/10.25560/97985
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Hamilton, Melissa Shea
Wilkinson, Robert
Levin, Michael
Sponsor/Funder: Royal College of Physicians of London
Wellcome Trust (London, England)
Francis Crick Institute
National Institutes of Health
Foundation for the National Institutes of Health
European Union
Funder's Grant Number: James Maxwell Grant Prophit Fellowship 2016
Wellcome Trust: 104803 and 203135
The Francis Crick Institute: FC0010218
National Institutes of Health: AI115940
FNIH: WILK116PTB
EDCTP2: SRIA2015-1065
Department: Infectious Disease
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Medicine (Research) MD (Res)
Appears in Collections:Medicine PhD theses



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