MEF2 targets and their functions in Drosophila immunity

感染会导致宿主发生许多变化。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，某些类型的白色血细胞会繁殖，以产生更有效的免疫反应。其中一些变化不是免疫系统特异性的，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，这些变化中的一些并不是纯粹的免疫系统特异性的，并且在对感染的反应中没有任何明显的功能-例如，在慢性疾病患者中经常看到的消耗综合征。所有这些变化最终都与免疫反应的激活有关，但通常很难理解将它们联系在一起的机制，也很难确定实际参与这些变化的许多基因。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，部分是因为它们可能为药物提供有用的新分子靶点，以对抗感染或减少病理，部分是因为了解这些基因如何共同作用以驱动它们的作用，可以开始告诉我们免疫反应的哪些方面在对抗哪些感染中实际上是重要的。通过研究果蝇（Drosophilamelanogaster）的感染，这一难题的重要组成部分。和人类一样，苍蝇在慢性感染时也会消瘦。我们发现一种名为MEF 2的蛋白质在果蝇脂肪细胞中有两种不同的作用。在没有感染的果蝇中，MEF 2对正常的能量储存很重要-脂肪细胞中MEF 2活性低的果蝇不能储存脂肪，并且异常瘦。当苍蝇被细菌感染时，MEF 2是正常免疫反应所必需的-脂肪细胞中MEF 2活性低的苍蝇会因多种感染而迅速死亡，因为它们无法引起免疫反应。重要的是，MEF 2的这两种不同功能是相互排斥的：使用MEF 2产生免疫反应的苍蝇不能使用MEF 2储存脂肪。这也是某些感染导致消瘦的部分原因，在新陈代谢和免疫之间的这种转换中，还有许多我们不了解的部分。特别是，我们知道MEF 2在每个过程中控制的一些基因，但我们不知道所有这些基因。这项计划的目标是确定MEF 2控制的健康和患病果蝇脂肪细胞中的所有基因。然后，我们将测试这些基因的功能-我们能识别出对免疫功能特别重要的基因吗？这也将帮助我们弄清楚如何在其他动物中识别MEF 2免疫靶点，比如人，这样我们就可以开始尝试判断MEF 2在人和苍蝇中的作用方式是否相同。

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.