MEF2 targets and their functions in Drosophila immunity

感染会引起宿主的许多变化。其中一些变化主要涉及免疫系统，纯粹是为了预防感染--例如，当人们受到感染时，某些类型的白细胞会繁殖，以产生更有效的免疫反应。其中一些变化不是免疫系统特有的，但显然可以帮助治愈感染-例如，发烧可以帮助清除入侵的病毒或细菌。最后，这些变化中的一些不是纯粹的免疫系统特有的，在应对感染方面没有任何明显的功能--例如，慢性病患者经常出现的消瘦综合症。所有这些变化最终都与免疫反应的激活有关，但总的来说，很难理解将它们联系在一起的机制，也很难准确定位许多实际参与这些变化的基因。尽管如此，了解调控这些过程的基因以及它们如何协同工作对我们来说是非常有用的，部分是因为它们可能为抗感染或减少病理的药物提供有用的新分子靶点，部分是因为了解这些基因如何协同工作来驱动它们所起的作用，可以开始告诉我们免疫反应的哪些方面在对抗哪些感染方面实际上是重要的。我们通过研究果蝇的感染发现了这个谜题的一个重要部分。像人一样，苍蝇在受到慢性感染时会逐渐消瘦。我们发现，一种名为MEF2的蛋白质在果蝇脂肪细胞中有两种不同的作用。对于没有感染的果蝇来说，MEF2对于正常的能量储存很重要--脂肪细胞中MEF2活性低的果蝇无法储存脂肪，而且异常苗条。当果蝇感染细菌时，正常的免疫反应需要MEF2--脂肪细胞中MEF2活性较低的果蝇会迅速死于多种感染，因为它们无法引发免疫反应。重要的是，MEF2的这两种不同功能是相互排斥的：使用MEF2产生免疫反应的苍蝇不能使用MEF2来储存脂肪。这是一些感染导致消瘦的部分原因。新陈代谢和免疫之间的这种转换仍然有许多我们不了解的部分。特别是，我们知道MEF2在每个过程中控制的一些基因，但我们不知道所有的基因。这项提议的目标是确定健康和患病果蝇脂肪细胞中MEF2控制的所有基因。然后我们将测试这些基因的功能--我们能否识别对免疫功能特别重要的基因？这也将帮助我们弄清楚如何在其他动物(如人)中识别MEF2免疫靶点，这样我们就可以开始尝试判断MEF2在人身上的作用方式是否与在苍蝇身上相同。

Infections cause many changes in their hosts. Some of these changes involve mostly the immune system and are oriented purely at preventing infection - for example, when people get infections, some kinds of white blood cells will multiply to make for a more effective immune response. Some of these changes are not immune-system specific, but can clearly help cure infection - for example, fevers can help clear invading viruses or bacteria. Finally, some of these changes are not purely immune-system specific, and don't serve any obvious function in the response to infection - for example, the wasting syndrome often seen in people with chronic illnesses. All of these changes are ultimately linked to the activation of the immune response, but in general it is hard to understand the mechanisms that link them together and it is hard to pinpoint many of the genes that are actually involved in these changes. Nonetheless, it is tremendously useful for us to understand the genes that regulate these processes and how they work together, partly because they may provide useful new molecular targets for drugs to fight infections or reduce pathology and partly because knowing how these genes work together to drive the effects they do can begin to tell us which aspects of the immune response are actually important in fighting which infections.We have found an important part of this puzzle by studying infections in a fruit-fly, Drosophila melanogaster. Like people, flies waste away when they have chronic infections. We have found that a protein called MEF2 has two different roles in fruit-fly fat cells. In flies that do not have an infection, MEF2 is important for normal energy storage - flies that have low MEF2 activity in their fat cells cannot store fat and are abnormally lean. When flies are infected with bacteria, MEF2 is required for a normal immune response - flies that have low MEF2 activity in their fat cells die rapidly, from many kinds of infections, because they cannot raise an immune response. Importantly, these two different functions of MEF2 are mutually exclusive: flies that are using MEF2 to generate an immune response cannot use MEF2 to store fat. This is part of the reason that some infections cause wasting.There are still many parts of this switch between metabolism and immunity that we do not understand. In particular, we know some of the genes that MEF2 controls in each process, but we do not know all of them. The goal of this proposal is to identify all the genes MEF2 controls in fat cells from healthy and sick flies. We will then test the functions of these genes - can we identify the genes that are particularly important for immune function? This will also help us figure out how to identify MEF2 immune targets in other animals, like people, so that we can begin to try to tell whether MEF2 works the same way in people as in flies.