Dectin-1-mediated suppression of protective anti-mycobacterial immunity

Dectin-1介导的保护性抗分枝杆菌免疫抑制

• 批准号: MR/W025779/1
• 负责人: Gordon Brown
• 金额: $ 77.46万
• 依托单位: UNIVERSITY OF EXETER
• 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%2FW025779%2F1
• 关键词: Dectin; mediated; suppression; protective; anti

Despite over a century of research, tuberculosis remains one of the deadliest bacterial infections in humans, resulting in over one-and-a-half million deaths each year. The important tools for combatting this global problem are the development of new anti-tubercular drugs and a more effective vaccine. Both depend, in large part, on obtaining a better understanding of the interactions between the human 'host' body and this bacterial microbe. We previously found a molecule on the surface of immune cells that senses microbes and activates host immune responses. We call this type of molecule a receptor. Remarkably, our new data now suggest that rather than being beneficial, the actions of this receptor actually increase susceptibility to infection with the bacterium that causes tuberculosis, M. tuberculosis (MTB). Our unpublished data also suggest that these detrimental effects occur, at least in part, through changes in the immune cell's ability to control bacterial growth. This discovery provides vital new insights into the factors underlying susceptibility to tuberculosis. Therefore, we propose to determine how this receptor negatively influences the protective immune responses and the extent to which this impacts human disease. To do this research, we will use experimental models of MTB infection in mice by comparing normal mice to mice which lack this receptor. We will examine important immune parameters that may be influenced by this receptor at different points during infection, and particularly after the immune system has had time to recognise and respond specifically to M. tuberculosis (known as the adaptive immune response). We will determine which receptor-expressing immune cells (or other cell types) play central roles in these responses. These experiments will allow us to understand how the receptor influences the immune response during infection. We will also use cell lines and tissue culture techniques to explore the role of this receptor in individual cells, to better understand how it mediates its functions (particularly its role controlling mycobacterial growth) and the mechanisms by which this receptor induces these responses. We will define exactly what the receptor is recognising (its ligand) on the surface of mycobacterial cells. These experiments will reveal the cellular mechanisms employed by the receptor. We will also determine whether this receptor functions in a similar manner in human cells. We will determine the effect of small genetic changes (called polymorphisms) in the human gene encoding this receptor. Such changes may have significant effects on receptor function and alter disease susceptibility in human populations. To summarise, we have discovered a receptor that promotes susceptibility to tuberculosis, and the experiments described here will provide substantial insights into the role and functions of this molecule in both mice and humans. The information we obtain in this project will allow us to gain a much better understanding of how MTB causes infection and will provide important scientific advances that will enable us to develop better treatments for people in the future.

尽管进行了一个多世纪的研究，但结核病仍然是人类最致命的细菌感染之一，每年导致超过一百多百万人死亡。解决这个全球问题的重要工具是开发新的抗结核药物和更有效的疫苗。在很大程度上，两者都取决于对人“宿主”身体与这种细菌微生物之间的相互作用的更好理解。我们先前在免疫细胞表面上发现了一个分子，可以感觉到微生物并激活宿主免疫反应。我们称这种类型的分子为受体。值得注意的是，我们的新数据现在表明，该受体的作用实际上不是有益，而是增加了对导致结核病的细菌感染的敏感性，结核分枝杆菌（MTB）。我们未发表的数据还表明，这些有害影响至少部分通过免疫细胞控制细菌生长的能力而发生。这一发现提供了对结核病敏感性的因素的重要新见解。因此，我们建议确定该受体如何负面影响保护性免疫反应以及这对人类疾病的影响程度。为了进行这项研究，我们将通过将正常小鼠与缺乏该受体的小鼠进行比较，在小鼠中使用MTB感染的实验模型。我们将检查重要的免疫参数，这些参数可能在感染期间在不同点上受到该受体的影响，尤其是在免疫系统有时间识别并特别响应结核分枝杆菌（称为适应性免疫反应）。我们将确定表达哪些受体免疫细胞（或其他细胞类型）在这些反应中起着核心作用。这些实验将使我们能够了解受体如何影响感染过程中的免疫反应。我们还将使用细胞系和组织培养技术来探索该受体在单个细胞中的作用，以更好地了解其如何介导其功能（尤其是其控制分枝杆菌生长的作用）以及该受体诱导这些反应的机制。我们将准确定义受体在分枝杆菌细胞表面识别的（其配体）。这些实验将揭示受体采用的细胞机制。我们还将确定该受体在人类细胞中是否以相似的方式起作用。我们将确定在编码该受体的人类基因中较小的遗传变化（称为多态性）的影响。这种变化可能会对受体功能产生重大影响，并改变人类人群中的疾病敏感性。总而言之，我们发现了一种促进结核病敏感性的受体，此处描述的实验将提供有关该分子在小鼠和人类中的作用和功能的实质性见解。我们在该项目中获得的信息将使我们能够更好地了解MTB如何引起感染，并将提供重要的科学进步，使我们能够在未来为人们开发更好的治疗方法。