Characterising the Pulmonary Innate Immune Response to Mycobacterium Tuberculosis and Evaluating the Role of Lung Microbiome in Determining Outcome

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Tuberculosis (TB) kills more people than any other single infectious disease. It is estimated that 1 in 4 people are infected with the bug that causes TB. We really need an effective vaccine to prevent people getting TB, but we don't understand what sort of immune response is needed to protect people.The very early response to infection, called the innate immune response, is not well understood in TB, partly because it is difficult to study, as most of the changes happen before people get symptoms. In a recent study I have worked on, we have seen that human infection with BCG, a bacteria similar to the one that causes TB, results in significant changes in the innate immune system in the airways which are not seen in the blood.The immune system is constantly coming into contact with different bacteria which live normally on the surfaces of our body (the microbiome). Understanding the interactions between the microbiome in the airways and TB will help us understand why some people can resist developing TB. This has led to the design of this study where for the first time we will look at this interaction between the microbiome in the airways, and the early innate immune response to TB which will help us to answer two key questions:1. What is the innate immune response to TB, and how does it vary?a. Is the immune system response to TB in the airways different to the blood?The immune response is different in different parts of the body. The airways are the first point of contact with the bacteria that causes TB and therefore it is important to understand what is happening early in the immune response there. We will use samples of sputum from deep inside the lung from people who have lived with people suffering from TB. We will measure the type of immune cells present and how they change over time, comparing what we find with blood results. This will help us to build a picture of what is happening in the airways early in the immune response to TB.b. Do differences in the immune system response help to explain why some people can fight off TB?The immune response to TB is also different in different people. Importantly, some people never develop a secondary (or 'adaptive') immune response. This may suggest that the initial innate immune response is sufficient in these individuals to clear all of the infection. We will therefore look for differences in the innate immune system between people who come into contact with TB and have evidence of a secondary immune response and those who don't. Understanding differences in the immune response would give us options to harness the power of the innate immune system when developing future vaccines.2. Does the microbiome of the airway help in protecting people from TB?The bacteria of the microbiome live in unison with our cells, and are able to survive without causing an infection which makes us unwell. It has increasingly been understood that these bacteria help to "train" our immune system to work better. We will look at which bacteria are living normally in the airways of the people recruited to our study, and see how these bacteria change over time. This will help us to answer several questions:a. Are there differences in the airway microbiome between people who get TB infection and those who don't?b. Does the microbiome of the airways change after TB infection occurs?c. Do differences in the airway microbiome explain differences in immune cells of the airways?d. Is there evidence that the immune system is being trained by the airway microbiome to fight off TB? In summary this study will look at the early immune response and the airway microbiome of people who have recently come into contact with the bacteria which causes TB. Differences which we find will help us explain why some people have protection from TB, and provide us with novel approaches to harness these changes to protect others from infection.