Defining immune mechanisms in silicotuberculosis

Abstract

Tuberculosis (TB) continues to be a leading cause of death worldwide, with over a million deaths annually. Furthermore, surivors of TB suffer continued morbidity which extends beyond TB treatment completion. Up to half of pulmonary TB (PTB) survivors have lasting lung health problems. People exposed to silica dust, through artisanal and small scale mining, which are prevalent in many high TB burden settings, are at particularly high risk of TB and also accelerated lung impairment and mortality from dual pathology due to TB and silicosis (silicotuberculosis).

This project builds on momentum following two international post-TB symposium to reinvigorate efforts to understand the pathophysiology of chronic lung disease due to TB, in the context of occupational silica dust exposure. After a period of laboratory training and review of the relevant literature, the successful applicant will develop an experimental model of silicotuberulosis, initially with a macrophage infection model with Mycobacterium tuberculosis (M.tb), building on experimental methods that have been developed to study immune responses in TB and HIV-TB. This work will help to identify how silica dust exposure modulates macrophage responses to M. tb. There will be the opportunity to validate in vitro findings, utilising samples from a clinical study of lung health in artisanal and small scale miners with TB, in Zimbabwe. This project will reignite an important area of study that has been long neglected since antimicrobial treatment regimens for TB were discovered, helping to inform the case for bespoke TB care pathways for miners exposed to silica and inclusion of mining populations specifically in TB treatment trials.

In this project, the successful applicant will use a variety of microbiological, immunological and molecular approaches to set up this model of a complex interaction. The supervisory team, across both the Department of Clinical Sciences (Dr Naomi Walker, Senior Clinical Lecturer) and Tropical Disease Biology (Dr Shaun Pennington, Lecturer in Infection and Immunology), combines laboratory and clinical expertise. Dr Walker is an academic committee chair of the international post-TB symposium, co-chair of the Liverpool TB multidisciplinary team meeting and has extensive experience in both laboratory and clinical TB research. Dr Pennington's research focus includes using advanced ex-vivo models for studies to investigate disease pathogenesis and host immune defence. The candidate will have the opportunity to travel overseas to support the parallel clinical study in a high TB burden setting, to gain experience of clinical research and the impact on TB-affected communities and will benefit from access to a dynamic group of collaborators. 

Where does the project lie on the Translational Pathway?

Expected Outputs

Training Opportunities

• microbiology, molecular biology (e.g. PCR), tissue culture and immunology
• study design, risk assessment and regulation
• data analysis
• working in biosafety level 3 facilities

In addition the student will gain experience in scientific writing, presenting and research communication and grant writing.

Skills Required

Key Publications associated with this project