Tuning the immune response in tuberculosis

Tuberculosis (TB) is an important infectious disease which affects nine million people and causes two million deaths every year. The human immune system can protect against TB but is also responsible for causing the tissue damage that may result from TB disease. I aim to increase our understanding of the parts of the immune system that influence the balance of beneficial and harmful responses to TB infection in order to identify new targets for more effective treatments and vaccines. To do this I will combine experiments in a fish model that closely resembles human TB with experiments in patients with active TB disease. Initially, I will focus on the role of a specific part of the immune system called interleukin (IL)10 because this is a key mediator that controls the immune system during its response to infections. Thus far the role of IL10 in TB has almost exclusively been evaluated in mouse models that provide incomplete information because they do not accurately reflect human TB disease. In addition, I will take advantage of the massive increase in genetic data that has become available, in order to discover new components of immune responses to TB which vary most between people. I postulate that variable immune responses cause differences in outcome of TB infection. I will test this theory by investigating the effects of deficiency or excess of potential new regulatory factors that I identify in people with TB, using the fish model of TB infection. I hope to gain new insights that help to develop novel interventions that will significantly shorten the length of anti-TB treatment, which will be important to reduce spread of TB and minimise development of drug resistance. I anticipate that my work may also lead to design of new vaccines that prevent TB disease altogether.

Understanding the molecular determinants that tune immune responses to provide effective control of mycobacterial growth without immunopathology is a key priority in tuberculosis (TB) research. I will combine transcriptional profiling of the tuberculin skin test (TST) for molecular level assessment of human anti-mycobacterial immune responses, with studies using the genetically tractable zebrafish Mycobacterium marinum (Mm) infection model to evaluate the role of a key immunoregulatory cytokine, interleukin (IL)10, in tuning the immune response in TB. I will also adopt a genome-wide discovery approach to identify novel regulators of human immune responses to Mycobacterium tuberculosis (Mtb), on the basis that variability in anti-mycobacterial responses is responsible for differences in pathogenesis. I will cross-reference genes within the TST that exhibit highly variable expression levels between different individuals, with data from recent functional genomic studies that describe putative genetic interactions, in order to identify key regulatory hubs. Functional effects of potential master-regulators on anti-mycobacterial immune responses will be investigated by genetic manipulation in the zebrafish Mm model. By selecting candidates based on variable human anti-mycobacterial immune responses and testing them using the zebrafish, which has a successful track record for modelling human TB, this cutting-edge strategy promises to elucidate novel pathways that tune immune responses to determine clinical outcome in TB. Importantly, this will inform development of adjunctive host-directed therapies to significantly shorten duration of standard anti-tuberculous chemotherapy, risk stratification of active disease in latent TB infection and strategies for design of novel anti-TB vaccines.

The principal impact of my proposed research will be to improve current understanding of immunological correlates of protection and pathogenesis in tuberculosis (TB). This work will be of broad interest to both the clinical and scientific community focussed on mycobacterial infection specifically, and infectious diseases more generally. Other investigators in the field will benefit from access to novel transcriptomic datasets incorporating immune responses to human and zebrafish mycobacterial infection, generated by my work to use for their own research.
Identifying pathways that can be targeted for personalised host directed therapy as an adjunct to standard chemotherapy in people with active TB is expected to significantly reduce morbidity and mortality associated with disease, by radically shortening treatment duration, preventing disease complications and improving efficacy of current antimicrobial regimens in those infected with drug resistant organisms. Short treatment regimens will promote better compliance with drug therapy, leading to reduced rates of drug resistance and TB transmission. Furthermore, my work will inform stratification of individuals who are latently infected for risk of developing active TB. This will ensure prophylactic therapy is only given to those at significant risk, for whom the benefits of treatment outweigh the risks of serious side effects, such as hepatotoxicity. This project will also potentially identify new vaccine targets that will facilitate rational design of much needed new, effective anti-TB vaccines to prevent disease altogether, which is particularly important in resource poor settings with high TB prevalence.
Infectious diseases impose a significant financial burden on the United Kingdom's economy. I anticipate that strategies to improve TB control that may arise as a result of my findings, will significantly reduce financial costs to both the health service and employers. Importantly, shorter treatment regimens will ensure less time lost from work and more rapid return to full productivity that will benefit both the national and global economy. In addition, minimising development of drug resistant TB will reduce the need for expensive, prolonged antibiotic courses and specialist inpatient care in this context.
My research will also form the scientific basis on which to update current guidelines for TB treatment. The ability to accurately predict progression to active disease in latently infected individuals will be of specific interest to policy makers with respect to developing evidence-based guidelines for treatment of latent TB.
Through my proposed programme of work and collaborations that I have recently initiated with Stephen Renshaw (Sheffield University) and Annemarie Meijer (Leiden University), I will acquire a broad range of new skills that will be invaluable in achieving my current and future research objectives. This fellowship will augment my transition to an independent investigator at the forefront of clinical and laboratory research in TB and respiratory tract inflammation and lays the foundations for obtaining a Senior Clinical Fellowship. In addition, the post-doctoral researcher appointed to work alongside me on this project will gain experience in a wide repertoire of laboratory techniques. They will also benefit from existing expertise in bioinformatic analysis within the host laboratory as well as frequent interactions with the dynamic academic community at UCL.