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.

Over 120,000 people in the USA and over 6000 people in the UK are waiting for organ transplants, and many more are suffering from organ failure. Many donor organs are not transplanted (approximately 60% of donor hearts and 20% of kidneys are not used), often because they can only be kept for a short time. Long term preservation would mean better matching with recipients over larger geographical areas, reducing the chances of rejection and increasing the number of organs that could be used. One potentially transformative method of preserving organs for a longer time is cryopreservation. This involves freezing the organs at very low temperatures and then defrosting them when needed. However, this is currently limited to small volumes (<3 ml), largely due to the difficulty in rewarming the tissues without damage after freezing. To avoid damage on rewarming, tissues must be heated quickly and uniformly. This is not possible with existing water bath methods so the development of new methods for volumetric rewarming of large tissue volumes is critical. The aim of this fellowship is to develop a novel method of tissue rewarming using ultrasound. As ultrasound passes through frozen tissue, it loses energy which is deposited as heat. By controlling the pattern of the ultrasound waves entering the tissue, heat can be deposited as needed to raise the temperature of the tissue quickly and uniformly. First, the ultrasound parameters will be optimised for maximum cell viability and optimal heating rate using small volumes of cells. An ultrasound array based on these parameters will then be developed with methods of steering and shaping the acoustic field to uniformly and rapidly heat larger volumes of cells. This will be extended to warming tissues with inhomogeneous acoustic and thermal properties and larger volumes, using real time feedback to control the heating distribution, with the ultimate vision of creating a fully flexible tool that can be used to rewarm whole organs. Ultrasonic volumetric warming has the potential to enable long-term storage of tissues and organs which would transform the availability of organs for transplant. It would also have many other applications such as increasing access to therapies involving implanting cells and tissues in the body for diseases such as type 1 diabetes or for restoration of fertility after cancer therapy.

Stents are used today to treat the blockages of the vessels of the heart in patients who have angina or suffered a heart attack. In most of these patients, stent treatment is effective and improves symptoms and life expectancy. However, there is a small proportion of patients where the stents fail and block, causing either death or a major heart attack. Studies in animals have shown that the blood flow patterns following stent implantation can predict stents that are at risk to block. However, there is lack of data about the role of blood flow on stent blockage in humans. This is because it is very difficult to create models of the vessels of the heart that have been treated with stents. This study aims to address this problem. We will analyse images of the vessels of the heart taken by a wire that is advanced in these vessels. In these images we can see details of the vessel wall and of the stent. We will use these images to create models of the vessels treated with stents using a new method that we have developed and then we will simulate blood flow in these models to assess the flow patterns. We will do that at scale in 120 patients of whom 40 had a heart attack because of a blocked stent. We will then compare the flow patterns in stents that blocked and caused a heart attack and in vessels treated with stents that did not cause an event. We believe that this research will allow us to identify the flow patterns that can cause stent blockage. This information is important as it will help us to improve the design of future stents and also the way that we put stents so as to reduce the risk of stent blockage and future heart attacks.