Host serum protein biomarkers of tuberculosis in sub-Saharan Africa

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.