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

结核病（TB）比任何其他单一传染病都要多。据估计，四分之一的人感染了导致结核病的细菌。我们确实需要一种有效的疫苗来预防人们感染结核病，但我们不知道需要什么样的免疫反应来保护人们。对感染的早期反应，称为先天免疫反应，在结核病中还没有得到很好的理解，部分原因是它很难研究，因为大多数变化发生在人们出现症状之前。在我最近的一项研究中，我们发现人类感染卡介苗（一种与结核病病原菌相似的细菌）会导致呼吸道中的先天免疫系统发生显著变化，而血液中则没有这种变化。免疫系统会不断与正常生活在我们身体表面的不同细菌（微生物组）接触。了解呼吸道中的微生物组与结核病之间的相互作用将有助于我们理解为什么有些人可以抵抗结核病的发展。这导致了本研究的设计，我们将首次研究气道中微生物组与结核病早期先天免疫反应之间的相互作用，这将有助于我们回答两个关键问题：1.什么是对结核病的先天免疫反应，它是如何变化的？a.免疫系统对肺结核的反应与血液不同吗？免疫反应在身体的不同部位是不同的。呼吸道是导致结核病的细菌的第一个接触点，因此了解那里的免疫反应早期发生了什么是很重要的。我们将使用肺深处的痰液样本，这些样本来自与结核病患者共同生活过的人。我们将测量存在的免疫细胞的类型以及它们如何随时间变化，将我们的发现与血液结果进行比较。这将有助于我们了解在对TB的免疫反应早期气道中发生了什么。免疫系统反应的差异是否有助于解释为什么有些人可以抵抗结核病？对结核病的免疫反应在不同的人身上也是不同的。重要的是，有些人从来没有发展出继发性（或“适应性”）免疫反应。这可能表明，这些个体的初始先天免疫应答足以清除所有感染。因此，我们将寻找与结核病接触并有二次免疫反应证据的人和那些没有的人之间先天免疫系统的差异。了解免疫反应的差异将为我们在开发未来疫苗时利用先天免疫系统的力量提供选择。呼吸道的微生物组是否有助于保护人们免受结核病的侵害？微生物组的细菌与我们的细胞和谐共存，能够在不引起感染的情况下生存，使我们感到不适。人们越来越多地了解到，这些细菌有助于“训练”我们的免疫系统更好地工作。我们将研究哪些细菌在我们研究招募的人的气道中正常生活，并观察这些细菌如何随时间变化。这将有助于我们回答几个问题：A。感染结核病的人和没有感染结核病的人之间的气道微生物组是否存在差异？B.肺结核感染发生后，气道的微生物组会发生变化吗？C.气道微生物组的差异是否可以解释气道免疫细胞的差异？D.是否有证据表明免疫系统正在接受气道微生物组的训练以抵抗结核病？总之，这项研究将着眼于最近接触过导致结核病的细菌的人的早期免疫反应和气道微生物组。我们发现的差异将有助于我们解释为什么有些人对结核病有保护作用，并为我们提供新的方法来利用这些变化来保护其他人免受感染。

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.