About the Project
A position is available for a strong, self-motivated PhD candidate within the TB Immunology laboratory at MRC Unit the Gambia at LSHTM. The candidate would be involved in a multi-site study to determine the long-term consequences of TB (TB-Sequel). The project will involve both cellular and molecular immunological techniques to understand the host immune response to TB and recovery post-treatment with a particular focus on lung inflammatory responses. The successful candidate will have an opportunity for significant training within MRCG and Germany.
Whilst not a restriction, preference will be given to applicants of African nationality and normally resident of a country in West and Central Africa. Applicants must have an MSc in immunology (or similar) obtained within the past 5 years, and appropriate research experience. This fellowship is a non-taxable generous stipend for 3 years.
Background
Despite apparent cure following standard TB therapy, a significant number of patients do not recover sufficient lung function and suffer from long-term sequelae. However, we cannot currently predict who will have a poor outcome. In order to facilitate the rational development of targeted host-directed therapies to prevent long-term sequelae, we require a better understanding of the underlying pathways leading to such adverse outcomes. Additionally, correlates of risk need to be identified at an early stage of TB treatment to enable cost-effective monitoring and intervention strategies.
This PhD project will be nested within a new project ‘TB-sequelae’ aimed at determining risk factors for sub-optimal outcome of TB therapy. This project has 5 research tasks incorporating epidemiology, microbiology, immunology, socio-economics and clinical cohort development. The PhD project will specifically relate to the Immunology and Microbiology research tasks but will link to the clinical cohort demographics for analysis.
The overarching objective of the project is to correlate longitudinal changes in host immune profiles with different clinical presentations and treatment outcome of TB patients. In particular, we will examine two key pathways associated with lung inflammation: insufficient glutathione (GSH) and excess matrix metalloprotease release (MMP); both of which can be readily targeted for host adjunctive therapies. We will analyse sputum and blood for gene signatures, cellular and soluble mediators in order to delineate predominant pathways of inflammation and to define prognostic biomarkers associated with differences in treatment response, lung function and long-term sequelae.
Hypothesis and Aims
We hypothesize that lung-sequelae correlate with exacerbated inflammation and tissue destruction prior to initiation of treatment and the severity of inflammation is influenced by other risk factors, such as HIV and smoking. We hypothesise that differences in the pathophysiology of TB, can be measured using relevant biomarkers in sputum and/or blood of TB patients. We hypothesise that levels of these markers or specific “disease associated signatures” indicate which inflammatory pathway(s) could be targeted with host adjunctive therapies to optimise outcomes and may predict outcome of TB treatment and subsequent long-term TB sequelae. Thus, our aims are to understand the pathophysiology and identify confounders for exacerbated lung damage leading to long-term clinical sequelae of TB patients and to define pre- or early-treatment biomarkers in blood/sputum that may predict treatment response and pulmonary outcome. This will allow us to determine the role of risk factors which could be amenable to preventive or therapeutic interventions with existing candidate products.
Objectives
Our co-primary objectives are: 1) to describe the impact of glutathione (GSH) deficiency and/or excessive matrix metalloproteases (MMPs) on lung inflammation, short and long-term lung function and outcome of TB treatment. 2) To correlate longitudinal changes in blood and lung (sputum) host biomarkers in TB patients with different treatment outcomes to define prognostic markers for ‘at-risk’ subjects.
Secondary Objectives
• To describe longitudinal changes in activation markers, soluble chemokines/cytokines, GSH and MMP in sputum and blood in relation to TB treatment outcome (microbiological and clinical)
• To correlate the markers described above with standard and novel microbiological tests
• To analyse the sputum and blood transcriptome in relation to TB treatment response (microbiological and clinical)
• To define early-onset prognostic biomarkers to detect subjects ‘at-risk’ for poor treatment outcome
Applications
Interested candidates can email [Email Address Removed] for the application form and guidance notes by April 3rd 2018.
Director of Studies: Dr. Jayne Sutherland, MRC Unit The Gambia at LSHTM
Co-Supervisor: Dr Christof Geldmacher, University of Munich
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