Cellular and transcriptomic analysis of regulatory T cells in streptococcal infection

这项提议涉及的是一群被称为“调节性T细胞？”的白细胞。(Tregs)。它们在体内的作用是抑制其他免疫细胞，防止炎症过度。我们希望研究他们在一种特殊的细菌感染环境中所做的事情：感染化脓性链球菌会导致从喉咙痛到猩红热、风湿性心脏病、败血症和坏死性筋膜炎(食肉疾病)等各种情况。我们知道，身体和这种细菌之间的相互作用是复杂的：一方面，需要强大的免疫反应来保卫身体，另一方面，许多疾病的表现本身就是过度免疫的结果。显而易见的是，特雷格很可能会发挥重要作用。Altmann实验室已经(在小鼠模型中)表明，在感染这种细菌的部位，Tregs及其相关分子的上调速度非常快。这项新提议的目的是开始建立对人类细胞中发生的事情的理解。该提案将新加坡和伦敦在这一领域具有高度互补性的调查人员聚集在一起？Altmann(Imperial)对链球菌败血症模型和Tregs的作用感兴趣，Rotzschke(Sign)参与了Tregs的详细细胞和分子分析，Yang(Sign)使用DNA微阵列技术描述免疫反应。后一种方法是一种非常有效的方法，它允许对以不同方式处理的细胞进行比较分析，方法是观察数万个人类基因，并询问在特定情况下，哪些基因被发现，哪些被拒绝。这三个团队将通过年度研讨会、每月视频会议以及在实验室之间派遣人员共同工作来建立密切的合作关系。中心组的实验依赖于从人类扁桃体中培养细胞，无论有没有Tregs，然后用不同毒力的不同版本的Strep感染培养物。我们将通过阵列分析，根据特定细胞群和基因逐个基因的存在情况，比较在有或没有Tregs的情况下发生的情况。我们将通过实验来支持这些人类研究，将Strep给予具有正常Tregs或已被基因敲除的小鼠。这些实验应该有助于更好地理解控制这些疾病的免疫事件。

This proposal is concerned with a population of white blood cells termed ?regulatory T cells? (Tregs). Their role in the body is to damp down other immune cells, preventing inflammatory ?overshoot?. We wish to examine what they do in a particular setting of bacterial infection: infections with Streptococcus pyogenes cause diverse conditions from sore throat to scarlet fever, rheumatic heart disease, sepsis and necrotising fasciitis (?flesh-eating disease?). We know that the interplay between the body and this bacterium is a complex one: on the one hand, a robust immune response is required to defend the body, while on the other, many of the disease manifestations are themselves a consequence of over-exuberant immunity. It is immediately apparent that there is likely to be an important role of Tregs. The Altmann lab has already shown (in mouse models) that there is a very rapid up-regulation of Tregs and molecules associated with them at the site of infection with this bacterium. The aim of this new proposal is to start building up an understanding of what happens in human cells. The proposal brings together investigators with highly complementary interests in this area in Singapore and London ? Altmann (Imperial) has been interested in models of streptococcal sepsis and the role of Tregs, Rotzschke (SiGN) has been involved in the detailed cellular and molecular analysis of Tregs, and Yang (SiGN) uses DNA microarray technology to describe immune responses. This latter approach is a very powerful one, allowing comparative analysis of cells that have been treated in different ways by looking at tens of thousands of human genes and asking, in a particular situation, which genes are turned up and which turned down. The 3 teams will build a close collaboration through annual workshops, monthly videoconferences, and by sending personnel between labs to work together. The central group of experiments depend on culturing cells from human tonsils, either in the presence or absence of Tregs, then infecting the cultures with various versions of Strep, of varying virulence. We will compare what happens, with or without Tregs, in terms of the presence of specific cell populations and gene by gene, though array anaysis. We will back up these human studies with experiments whereby we give the Strep to mice that either have normal Tregs, or have had them genetically knocked out. These experiments should lead to an improved understanding of the immunological events controlling these diseases.