Sickness behavior: causes and functional consequences

疾病行为：原因和功能性后果

• 批准号: BB/L020122/2
• 负责人: Marc Dionne
• 金额: $ 27.82万
• 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=BB%2FL020122%2F2
• 关键词: Sickness; behavior; causes; functional; consequences

All animals exhibit behavioral changes due to infection. Conspicuously, some of these changes are quite general: for example, people and other animals with a very wide variety of different infections tend to show reduced appetite and disruptions to circadian behaviors (like sleep). These general effects of infections on behavior are broadly called "sickness behaviors". Sickness behaviors have significant effects on human health and well-being, but they also have real costs in other animals. For example, reduced feeding due to infections in cattle reduces beef quality and quantity, and similar effects exist in other livestock.The fact that sickness behaviors are so widespread among animals suggests that they must be an important part of the immune response, but we know relatively little about their actual function. We also know relatively little about their cause, in most cases: many different signals are produced by the immune system in response to infection, and most of these signals have effects on the nervous system, but the actual specific immune signals responsible for any particular sickness behavior tend to be difficult to pin down.The experiments we propose to perform here focus on two sickness behaviors-reduced feeding and circadian disruption-in a fruit-fly. We have found a specific gene that is turned on in the fruit-fly in response to infections. This gene produces a signal that is received by brain cells. We have found that this signal makes the fruit-fly eat less when it has an infection. One aspect of the work we propose here is to understand how infections turn on this signal, and where the signal is coming from-for example, is it coming from blood cells or brain cells? This is important for the fly because flies that cannot receive this signal have reduced ability to fight infections; it is important for people and other mammals because we also produce the same signal in response to infections. Understanding how this signal is turned on, what cells produce it, and its functions in the fruit-fly will help us understand what kinds of changes can be generated by the same signals in humans and how we can manipulate these signals to promote better immune competence or less disease pathology.We also would like to understand why it is important that we eat less when we are sick. Our laboratory has previously shown that fruit-flies, like people, alter their metabolic activity in response to infections; we have recently discovered that the fruit-fly must shut down critical energy-storage functions in order to raise a productive immune response. One way to shut down energy storage is to eat less. Thus, our prior work suggests that sickness behaviors might be directly required to produce an immune response. The work we propose to do here will test this: we will learn how important reduced feeding actually is in generating a functional immune response. This kind of experiment is difficult and expensive in mammals, but it is comparatively easy and quick in flies, and it will allow us to ask more-focused questions in experiments on humans and mice.

所有动物都因感染而表现出行为变化。显然，其中一些变化是相当普遍的：例如，患有各种不同感染的人和其他动物往往表现出食欲下降和昼夜节律行为（如睡眠）中断。感染对行为的这些一般影响被广泛地称为“疾病行为”。病态行为对人类的健康和幸福有着显著的影响，但它们也会给其他动物带来真实的代价。例如，由于牛的感染而减少喂养会降低牛肉的质量和数量，其他牲畜也存在类似的影响。疾病行为在动物中如此普遍的事实表明，它们一定是免疫反应的重要组成部分，但我们对它们的实际功能知之甚少。我们对它们的原因也知之甚少，在大多数情况下：免疫系统对感染作出反应时会产生许多不同的信号，并且这些信号中的大多数对神经系统有影响，但是，导致任何特定疾病行为的实际特定免疫信号往往很难确定。我们建议在这里进行的实验集中在两种疾病行为上-减少进食和昼夜节律紊乱-在一个果蝇。我们已经发现了一种特殊的基因，这种基因在果蝇对感染的反应中被打开。这种基因产生一种信号，被脑细胞接收。我们发现，这种信号使果蝇在感染时吃得更少。我们在这里提出的工作的一个方面是了解感染如何打开这个信号，以及信号来自哪里-例如，它是来自血细胞还是脑细胞？这对苍蝇很重要，因为不能接收到这种信号的苍蝇抵抗感染的能力会降低;这对人类和其他哺乳动物很重要，因为我们在应对感染时也会产生相同的信号。了解这种信号是如何开启的，是什么细胞产生这种信号，以及它在果蝇中的功能，将有助于我们了解人类体内同样的信号会产生什么样的变化，以及我们如何操纵这些信号来促进更好的免疫能力或减少疾病病理，我们还想知道为什么我们生病时少吃很重要。我们的实验室以前已经表明，果蝇，像人一样，改变他们的代谢活动，以应对感染;我们最近发现，果蝇必须关闭关键的能量储存功能，以提高生产性免疫反应。因此，我们先前的研究表明，生病的行为可能是产生免疫反应的直接条件。我们在这里要做的工作将测试这一点：我们将了解减少进食在产生功能性免疫反应中的重要性。在哺乳动物身上进行这种实验既困难又昂贵，但在苍蝇身上进行这种实验相对容易和快速，这将使我们能够在人类和小鼠的实验中提出更集中的问题。

项目成果

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