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

尽管经过了一个多世纪的研究，结核病仍然是人类最致命的细菌感染之一，每年导致超过150万人死亡。对抗这一全球性问题的重要工具是开发新的抗结核药物和更有效的疫苗。两者在很大程度上都依赖于更好地了解人类“宿主”身体与这种细菌微生物之间的相互作用。我们之前在免疫细胞表面发现了一种分子，可以感知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，这种受体的作用非但不是有益的，反而增加了感染引起结核病的细菌--结核分枝杆菌(MTB)的易感性。我们未发表的数据也表明，这些有害影响至少部分是通过免疫细胞控制细菌生长能力的变化而发生的。这一发现为结核病易感性的潜在因素提供了至关重要的新见解。因此，我们建议确定这种受体如何对保护性免疫反应产生负面影响，以及这种影响对人类疾病的影响程度。为了进行这项研究，我们将使用小鼠感染结核杆菌的实验模型，将正常小鼠与缺乏这种受体的小鼠进行比较。我们将在感染期间的不同时间点检查可能受到该受体影响的重要免疫参数，特别是在免疫系统有时间识别和特异性地对结核分枝杆菌做出反应(称为适应性免疫反应)之后。我们将确定哪些表达受体的免疫细胞(或其他细胞类型)在这些反应中发挥核心作用。这些实验将使我们了解受体在感染过程中如何影响免疫反应。我们还将使用细胞系和组织培养技术来探索这种受体在单个细胞中的作用，以更好地了解它如何调节其功能(特别是它控制分枝杆菌生长的作用)以及这种受体诱导这些反应的机制。我们将准确地定义受体在分枝杆菌细胞表面识别的内容(其配体)。这些实验将揭示该受体使用的细胞机制。我们还将确定这种受体是否在人类细胞中以类似的方式发挥作用。我们将确定编码这种受体的人类基因的微小遗传变化(称为多态)的影响。这些变化可能会对受体功能产生重大影响，并改变人类群体中的疾病易感性。总而言之，我们已经发现了一种促进结核病易感性的受体，这里描述的实验将为这种分子在老鼠和人类中的作用和功能提供实质性的见解。我们在这个项目中获得的信息将使我们能够更好地了解结核杆菌是如何引起感染的，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。

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 Our unpublished data also suggest that these detrimental effects occur, at least in part, through changes in the immune cell's ability to control bacterial growth.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.