Academics in the LTBRG are aiming to identify new drug targets by focusing on the physiology and transmission of mycobacterium.
- How does M. tuberculosis respond to their environment?
- How does M. tuberculosis utilise nutrients effectively?
- How do modifications of M. tuberculosis physiology contribute to success?
Our key areas of research
- Clinical disease expression
- Characterising bacterial physiology phenotypes
- Defining immunological markers of disease
- Defining complex relationships that exist between these domains
- Discovery of novel drug and diagnostic/prognostic targets
- Determination of immune responses that inform vaccine development
- Determination of biomarkers to characterise host-pathogen relationship
This research is focused on phenotypic resistance of Mycobacterium tuberculosis which can be seen as phenotypic tolerance and which results in ‘persistent’ populations. This group discovered dormant M. tuberculosis populations in sputum which has enabled us to estimate ‘persister’ populations in patients and map these to clinical responses. We are developing approaches to target these populations using high throughput screens. Other research focuses on determining the factors which allow bacteria to sense and respond to stressful environments (i.e. immune or drug related stress) in order to identify drug targets.
Mycobacterial Physiology and Transmission
This research is focused on how bacteria respond to their environment, how they utilise nutrients and how they modify their physiology to achieve success. Factors which increase adaptation to humans and the influence of these factors on effective transmission are being studied.
Leicester TB services clinical team has a strong scientific interest in the prevention of TB through rapid access to services and through systematic screening for latent TB infection (LTBI) of risk groups and preventative treatment strategies. There is a strong focus on the development and utilisation of bespoke IT infrastructure to collate clinical data for both service delivery and cohort characterisation in prospective observational and interventional studies. The LTBRG is investigating determinants of TB progression from LTBI, development of cost-effective screening strategies for LTBI, safe preventative treatment for LTBI, effective prevention of LTBI and specialty-led/database-based electronic medical records.
The identification and prevention of LTBI in high-risk populations – most notably recent contacts, migrants from high TB incidence areas and those with HIV infection – is being studied in a prospective longitudinal framework. Data from this work is contributing to the development of effective international and national health policy for TB prevention and informing strategies for effective engagement with vulnerable and ethnic minority groups with specific health needs. Study of TB prevention strategies and the epidemiology of M. tuberculosis infection, with a particular focus on the utility of diagnostic tools for characterising future TB risk and their implementation in screening programs completes the areas of focus for this team.
This program integrates with the bacteriology and the clinical research programs to provide tools and models with which to define the factors which impact TB disease pathogenesis. Experimental medicine studies using the well-defined cohorts generate hypotheses which are tested using in vitro and in vivo models of infection in an iterative manner. The focus of the group is to define immunological parameters which indicate disease progression and treatment success. It also focuses on identifying the critical parameters which define T cells capable of mediating immunity to TB.
Case study: TB immune responses
An infection model was developed that consists of a low dose mycobacterial challenge, through droplet particles, to the alveolar tissue in the lung. This model allows for very early immune-mediated events in the lung tissue to be dissected regarding kinetics, location and the contribution of specific cell types to immunity. There has been a focus on the role of IL-12, IL-23 and IL-17 and the specific role of dendritic cells and lung resident innate lymphocytes in initiation and coordination of the acquired T cell response. This work was carried out by Professor Andrea Cooper.