Investigating local determinants of outcome in human tuberculosis

研究人类结核病结果的局部决定因素

• 批准号: MR/W025728/1
• 负责人: Paul Elkington
• 金额: $ 99.08万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW025728%2F1
• 关键词: Investigating; local; determinants; outcome; human; Investigating; local; determinants; outcome; human

Tuberculosis is an infection which kills approximately one and a half million people each year, and is becoming increasingly resistant to the antibiotics used to treat it. A central challenge in understanding tuberculosis is that the body's immune response is needed to control infection, but also causes the inflammation that leads to lung damage and spread of infection. In addition, in the same individual, some areas of infection can progress whilst other regress, indicating that it is local factors that determine outcome. Tuberculosis is exclusively a disease of humans, and therefore to fully understand this complex interaction requires a human laboratory system that can be studied to determine the underlying processes.We have developed an entirely new way of investigating infection in the laboratory by developing a method where we infect human cells and then encapsulate them into mini-spheres for long-term analysis. This has the benefit that we can monitor the infection for much longer than the usual laboratory systems, and we have shown that key features like the behaviour of human cells and the response to antibiotics is more similar to that observed in patients than traditional systems. In this programme of work, we will use two different but complementary approaches to determine what regulates the outcome of tuberculosis infection in individual lesions. First, we will modify the mini-sphere environment and composition to determine which factors lead to optimal control of infection. We will add inflammatory mediators around the spheres and measure the progress of infection. Next, we will modulate the number and activation of immune cells that we encapsulate in the mini-spheres. Finally, we will change the fibres within the spheres. Together, these experiments will tell us which conditions help the immune system control infection most effectively.In parallel, we will design a highly sensitive camera system, which allows us to measure infection within each mini-sphere, as the bacteria have been genetically modified to spontaneously produce light. We will measure the progress of infection over time, and then study the cells within mini-spheres where infection is being controlled versus those where the infection is progressing. We will extract the cells and measure their activation using the latest single cell profiling techniques, to understand which characteristics are needed to control infection. Finally, we will study tissue from patients with tuberculosis, again comparing progressive and controlling lesions, to confirm our observations in mini-spheres at the site of disease in patients.Taken together, our findings will tell us why some tuberculosis lesions progress and some regress, which is essential knowledge to inform new strategies such as vaccination and lung-protective treatments to control the global epidemic.

结核病是一种感染，每年可杀死大约一百万人，并且对用于治疗的抗生素越来越抗性。理解结核病的一个核心挑战是，需要人体的免疫反应来控制感染，但也会引起炎症，从而导致肺部损伤和感染的传播。此外，在同一个人中，某些感染领域可以进展，而其他回归，表明正是局部因素决定了结果。结核病仅是人类的一种疾病，因此为了充分理解这种复杂的相互作用，需要一个可以研究的人类实验室系统来确定基本过程。我们通过开发一种方法，通过开发一种方法，通过开发一种我们感染人类细胞，然后将它们封装成长期分析的方法，从而开发了一种全新的研究方法。这有一个好处，我们可以比通常的实验室系统监测感染更长的时间，并且我们表明，诸如人类细胞的行为和对抗生素的反应之类的关键特征比在患者中观察到的关键特征比传统系统更相似。在这个工作计划中，我们将使用两种不同但互补的方法来确定哪种调节单个病变中结核病感染的结果。首先，我们将修改迷你球形环境和组成，以确定哪些因素导致最佳控制感染。我们将在球体周围添加炎症介体并测量感染的进展。接下来，我们将调节封装在迷你球体中的免疫细胞的数量和激活。最后，我们将改变球体内的纤维。这些实验将共同告诉我们哪些条件有助于免疫系统控制感染。同时，我们将设计一个高度敏感的摄像机系统，这使我们能够在每个微型球员中测量感染，因为细菌已被基因修饰以自发产生光。我们将随着时间的推移测量感染的进展，然后研究在控制感染与感染进展的细胞中的细胞。我们将使用最新的单细胞分析技术提取细胞并测量它们的激活，以了解控制感染需要哪些特征。最后，我们将研究结核病患者的组织，再次比较进行性和控制病变，以确认我们在患者疾病部位的迷你球形中的观察结果。一起，我们的发现将告诉我们为什么一些结核病病变的进展和一些回归，这是一些基本知识，这是诸如疫苗接种和肺部保护的新策略，以控制全球保护和全球性的范围。