Every year, two million people die from tuberculosis, and the immune system itself is partly to blame—it can protect against the bacteria but also damages lung tissue in the process. This project aims to untangle that double-edged response by studying a fish model that mimics human TB more accurately than standard mice, alongside blood samples from patients with active disease. The researcher focuses first on a signalling molecule called interleukin-10, which controls immune activity during infection but has mostly been studied in mouse models that poorly reflect human TB. They will also mine large genetic datasets to find new immune components that vary between people, then test whether too much or too little of those components changes disease outcomes in the fish model. If successful, this work could identify targets for treatments that shorten the current six-month antibiotic regimen—reducing the risk of drug resistance and spread—and may also guide the design of vaccines that prevent TB entirely.
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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.
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