mTOR control of effector CD4+ T cell activation during malaria infection

在世界许多地区，疟疾感染仍然是人类发病和死亡的一个重要原因。目前，我们仍然不完全理解为什么一些人能够免受严重疟疾的伤害，这些疾病的症状包括呼吸窘迫、贫血和脑病理，以及为什么其他人，特别是幼儿、孕妇和半免疫成年人非常容易受到感染。然而，越来越多的证据表明，感染的许多严重并发症并不是由寄生虫本身直接造成的，而是在很大程度上由个人对寄生虫的反应方式及其产生的免疫反应的性质决定的。对寄生虫产生非常强的促炎免疫反应的个体似乎比炎症反应较低的个体患严重疟疾的风险要高得多。身体敏感区域内强烈的促炎免疫反应可能导致器官损伤，在极端情况下，甚至死亡。疟疾(和许多其他)感染的成功解决似乎取决于允许产生足够的免疫反应来杀死寄生虫，然后在这些反应变得太强并导致组织损伤之前抑制这些反应。人体如何识别感染期间抑制对寄生虫的炎症反应的正确时间，以及炎症细胞被指示变得不那么炎性的途径，人们还知之甚少。在这项建议中，我们的目标是解决一种特定的免疫细胞群，称为效应器CD4+T细胞，它可以产生大量的促炎介质，并在疟疾感染期间直接造成组织损伤。现在已经知道，CD4+T细胞需要通过处理葡萄糖和氨基酸(一个称为新陈代谢的过程)来产生大量的能量来引起炎症，而炎症程度较低的CD4+T细胞需要的能量要少得多。效应器CD4+T细胞的代谢在很大程度上是由哺乳动物雷帕霉素(MTOR)复合体调控的，该复合体位于CD4+T细胞内。至关重要的是，我们已经证明，在疟疾感染的早期阶段，mTOR在CD4+T细胞中高度激活，这表明mTOR促进了效应器CD4+T细胞的激活，但在感染后期CD4+T细胞中的活性较低。因此，我们的数据表明，在疟疾感染过程中，效应器CD4+T细胞代谢和mTOR活性下调，这可能是CD4+T细胞引起炎症的能力降低的主要原因。在这个项目中，我们将使用一系列技术详细研究疟疾感染过程中CD4+T细胞的代谢情况，并讨论mTOR及其相关途径在确定效应者CD4+T炎症功能中的功能重要性。随后，我们将在疟疾感染的不同阶段改变效应分子CD4+T细胞的代谢，并评估这对控制疟疾感染的影响。最后，我们将确定在疟疾感染过程中影响mTOR激活和影响CD4+T细胞代谢的各种免疫信号。我们的项目将提供第一个关于在疟疾感染期间CD4+T细胞如何同时对其环境和免疫信号做出反应的综合概述。该项目的结果将大大提高我们对疟疾感染期间促炎免疫反应是如何调节的理解。这一知识应有助于对有严重疾病风险的个人进行更准确的预后，但也应有助于开发可用于治疗严重疟疾患者的辅助疗法。我们预计，我们的发现也将与许多其他急性传染病的理解和治疗直接相关。

Malaria infection remains a significant cause of morbidity and mortality in humans in many regions of the world. At present we still do not fully understand why some individuals are protected from severe malarial disease, symptoms of which include respiratory distress, anaemia and cerebral pathology, and why others, in particular young children, pregnant women and semi-immune adults, are very susceptible to infection. Accumulating evidence, however, suggests that many of the severe complications of infection are not caused directly by the parasite itself but are, in large part, determined by the way an individual responds to the parasite and the nature of the immune response that they develop. An individual that mounts a very strong pro-inflammatory immune response to the parasite appears to be at much higher risk of developing severe malarial disease than an individual who mounts a lower inflammatory response. Strong pro-inflammatory immune responses within sensitive areas of the body may lead to organ damage and in extreme cases, death. Successful resolution of malaria (and many other) infections appears to depend upon allowing a sufficient immune response to develop to kill parasites, but then suppressing these responses before they become too strong and cause tissue damage. How the body identifies the correct time during infection to dampen the inflammatory response to the parasite, and the ways through which inflammatory cells are instructed to become less inflammatory, are poorly understood. In this proposal we aim to address how a specific population of immune cells, called effector CD4+ T cells, which can produce copious amounts of pro-inflammatory mediators and directly cause tissue damage during malaria infection, are regulated. It is now known that CD4+ T cells need to generate huge amounts of energy through processing glucose and amino acids (a process called metabolism) to cause inflammation whereas CD4+ T cells that are less inflammatory require far less energy. Effector CD4+ T cell metabolism is largely controlled by the mammalian target of Rapamycin (mTOR) complex, which is located inside the CD4+ T cell. Crucially, we have shown that mTOR is highly activated in CD4+ T cells during the early stages of malaria infection, suggesting that mTOR promotes effector CD4+ T cell activation but is less active in CD4+ T cells during the latter stages of infection. Thus, our data suggests that effector CD4+ T cell metabolism and mTOR activity is downregulated during the course of malaria infection and that this may be a major reason for the reduction in the ability of CD4+ T cells to cause inflammation. In this project we will investigate in detail using a spectrum of techniques the metabolic profile of CD4+ T cells during the course of malaria infection and we will address the functional importance of mTOR and related pathways in determining effector CD4+ T inflammatory function. Subsequently we will modify effector CD4+ T cell metabolism at various stages of malaria infection and assess the impact of this on the control of malaria infection. Finally, we will identify the various immunological signals that modify mTOR activation and effector CD4+ T cell metabolism during malaria infection. Our project will provide the first integrated overview of how CD4+ T cells simultaneously respond to their environment and immunological signals during malaria infection. The results from this project will significantly increase our understanding of how pro-inflammatory immune responses are regulated during malaria infection. This knowledge should lead to more accurate prognosis of individuals at risk of severe disease but should also inform the development of adjunct therapies that can be used to treat individuals with severe malaria. We expect that our findings will also be directly relevant to the understanding and treatment of many other acute infectious diseases.