MEF2 targets and their functions in Drosophila immunity

MEF2 靶标及其在果蝇免疫中的功能

• 批准号: MR/L018802/2
• 负责人: Marc Dionne
• 金额: $ 34.96万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL018802%2F2
• 关键词: MEF2; targets; their; functions; Drosophila

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.

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，某些种类的白细胞会繁殖，以产生更有效的免疫反应。其中一些变化不是免疫系统特异性的，但显然可以帮助治疗感染——例如，发烧可以帮助清除入侵的病毒或细菌。最后，其中一些变化并不完全是免疫系统特异性的，在对感染的反应中没有任何明显的功能——例如，慢性疾病患者经常出现的消耗综合征。所有这些变化最终都与免疫反应的激活有关，但总的来说，很难理解将它们联系在一起的机制，也很难确定实际上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对我们来说是非常有用的，部分原因是它们可能为药物提供有用的新分子靶标，以对抗感染或减少病理，部分原因是了解这些基因如何协同工作以驱动它们所做的效果，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。我们通过研究一种名为黑腹果蝇（Drosophila melanogaster）的果蝇的感染，发现了这个谜题的重要部分。和人一样，苍蝇在受到慢性感染后也会消瘦。我们发现一种叫做MEF2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，MEF2对正常的能量储存很重要——脂肪细胞中MEF2活性低的果蝇不能储存脂肪，并且异常消瘦。当苍蝇被细菌感染时，正常的免疫反应需要MEF2——脂肪细胞中MEF2活性低的苍蝇会因多种感染而迅速死亡，因为它们不能引起免疫反应。重要的是，MEF2的这两种不同功能是相互排斥的：使用MEF2产生免疫反应的果蝇不能使用MEF2储存脂肪。这是一些感染导致消耗的部分原因。在新陈代谢和免疫之间的这种转换中，还有许多部分是我们不了解的。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（如人类）中识别MEF2的免疫靶标，这样我们就可以开始尝试判断MEF2在人类身上的作用方式是否与在苍蝇身上一样。

项目成果

fs(1)h controls metabolic and immune function and enhances survival via AKT and FOXO in Drosophila.

fs(1)h 在果蝇中通过 AKT 和 FOXO 控制代谢和免疫功能并提高存活率。

• DOI: 10.1242/dmm.037259
• 发表时间: 2019
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Sharrock J

Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster.

肌动蛋白是一种进化上保守的损伤相关分子模式，可发出果蝇组织损伤的信号。

• DOI: 10.7554/elife.19662
• 发表时间: 2016
• 期刊: eLife
• 影响因子: 7.7
• 作者: Srinivasan N

Infection increases activity via Toll dependent and independent mechanisms in Drosophila melanogaster

感染通过 Toll 依赖和独立机制增强果蝇的活性

• DOI: 10.1101/2021.08.24.457493
• 发表时间: 2021
• 作者: Vincent C

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection.

• DOI: 10.1038/ncomms14642
• 发表时间: 2017-03-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Péan CB;Schiebler M;Tan SW;Sharrock JA;Kierdorf K;Brown KP;Maserumule MC;Menezes S;Pilátová M;Bronda K;Guermonprez P;Stramer BM;Andres Floto R;Dionne MS
• 通讯作者: Dionne MS

Infection increases activity via Toll dependent and independent mechanisms in Drosophila melanogaster.

• DOI: 10.1371/journal.ppat.1010826
• 发表时间: 2022-09
• 期刊: PLoS pathogens
• 影响因子: 6.7