A bovine alveolus model to replace cattle in the study of host-pathogen interactions in bovine tuberculosis

牛肺泡模型替代牛用于牛结核病宿主与病原体相互作用的研究

• 批准号: NC/M002047/1
• 负责人: Mark Chambers
• 金额: $ 54.13万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FM002047%2F1
• 关键词: bovine; alveolus; model; replace; cattle

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis (BTB) and infects livestock with severe socio-economic consequences and an impact on animal health. As well as the financial and emotional impact BTB has on the cattle farming community and government, the disease is a major risk to human and livestock health in developing countries. The control of BTB has proved problematic in Great Britain and Ireland. In the absence of improved control the projected economic burden to GB over the next decade is predicted to be £1 billion.Tackling BTB requires deeper insights into host-pathogen interactions otherwise it is unlikely any major breakthroughs in developing effective tools for disease intervention will occur. The principle route of infection with M. bovis is via inhalation of infectious aerosols. On inhalation, M. bovis reaches the lung tissues, especially the alveolus. What happens next determines whether the host goes on to acquire TB, or whether the host deals with the threat. Research in human TB shows that epithelial cells lining the alveolus are far more than a simple physical barrier to pathogens. Indeed, M. tuberculosis is able to penetrate these cells and gain access to the deeper tissues whilst evading elimination by the immune system. In turn, the epithelium detects the presence of mycobacteria, responding by producing molecules involved in antimicrobial activity, inflammation, and pathology. As the lung epithelium is central to early response to TB, better understanding of the early events and interactions that occur when virulent mycobacteria arrive in the bovine alveolus are needed. No model currently exists with which to conduct these studies and the crucial events in the earlier stages of infection are intractable for study in the live animal. Understanding early events that are played out within the alveolus is critical if we are to gain new insights in how to enhance host resistance to infection, e.g. through vaccination. In response to this need, we shall develop a tissue culture model of the bovine alveolus with which to study the interaction of M. bovis with the bovine host. The model represents a non-animal alternative with which to study of the pathogenesis of BTB by removing the need to infect cattle with mycobacteria to answer fundamental questions in TB pathogenesis and provide a valid substitute for cattle that can be used by researchers without access to animal facilities. The simplicity of the model make it preferable over the use of the whole animal, and for answering questions that require data to be gathered within minutes of infection or where time course studies are required. This will be a new tool available to the scientific community. Its use is not confined to BTB, but would be applicable to the study of respiratory infections of cattle in general, many of global importance, such as bovine respiratory disease (BRD). Vaccines against BTB developed to generate a specific host response would be a significant advance on the current state of affairs where vaccines must be tested empirically in cattle to evaluate their efficacy. A specific objective of this project will determine whether the behaviour of BCG / M. bovis and host cells in the model correlates with protective efficacy seen in cattle challenge studies from which we have stored blood cells to evaluate. Identifying a read-out in our model that is related to vaccine efficacy in the whole animal could be a basis of screening vaccine candidates without the need to challenge cattle with M. bovis. This would reduce the severity and duration of animal experiments, as well as significantly reduce their cost. We hypothesise that a significant aspect of vaccine-mediated protection against BTB is expressed at the level of host-pathogen interactions within the alveolus.

牛分枝杆菌(M.bovis)是牛结核病(BTB)的病原体，感染家畜具有严重的社会经济后果和动物健康。除了BTB对养牛业社区和政府造成的经济和情感影响外，这种疾病还对发展中国家的人类和牲畜健康构成重大威胁。事实证明，英国和爱尔兰对BTB的控制存在问题。在没有更好的控制的情况下，预计未来十年英国的经济负担将达到10亿GB。限制BTB需要对宿主与病原体的相互作用有更深入的了解，否则在开发有效的疾病干预工具方面不太可能取得任何重大突破。感染牛分枝杆菌的主要途径是吸入传染性气雾剂。吸入时，牛分枝杆菌可到达肺组织，尤其是肺泡。接下来发生的事情决定了主机是否会继续感染结核病，或者主机是否会应对威胁。对人类结核病的研究表明，肺泡内的上皮细胞远远不止是抵御病原体的简单物理屏障。事实上，结核分枝杆菌能够穿透这些细胞并进入更深的组织，同时躲避免疫系统的清除。反过来，上皮细胞检测分枝杆菌的存在，通过产生参与抗菌活动、炎症和病理的分子来做出反应。由于肺上皮细胞是结核病早期反应的中心，因此需要更好地了解当毒力分枝杆菌到达牛肺泡时发生的早期事件和相互作用。目前还不存在进行这些研究的模型，感染早期的关键事件很难在活体动物中进行研究。如果我们要在如何增强宿主对感染的抵抗力方面获得新的见解，例如通过接种疫苗，了解肺泡内发生的早期事件是至关重要的。针对这一需要，我们将建立一种牛肺泡组织培养模型，用来研究牛分枝杆菌与牛宿主的相互作用。该模型代表了一种研究牛结核病发病机制的非动物替代方法，它消除了用分枝杆菌感染牛的需要，以回答结核病发病机制的基本问题，并提供了一种有效的牛替代品，研究人员可以在没有动物设施的情况下使用牛。该模型的简单性使其比使用整个动物更可取，并适用于回答需要在感染后几分钟内收集数据的问题或需要进行时间进程研究的问题。这将是科学界可用的新工具。它的用途不仅限于牛结核病，而且将适用于一般牛的呼吸道感染的研究，许多具有全球重要性，如牛呼吸道疾病(BRD)。为产生特定宿主反应而开发的针对BTB的疫苗将是对目前情况的重大进步，目前必须对疫苗在牛身上进行经验测试，以评估其效果。该项目的一个具体目标将确定卡介苗/牛分枝杆菌和宿主细胞在模型中的行为是否与我们储存血细胞进行评估的牛挑战研究中看到的保护效果相关。在我们的模型中识别与整个动物的疫苗效力相关的读数，可以作为筛选候选疫苗的基础，而不需要用牛分枝杆菌来挑战牛。这将减少动物实验的严重性和持续时间，并显著降低其成本。我们假设，疫苗介导的针对BTB的保护的一个重要方面是在肺泡内宿主-病原体相互作用的水平上表达的。