Sickness behavior: causes and functional consequences

所有动物都因感染而表现出行为上的改变。值得注意的是，其中一些变化非常普遍：例如，患有各种不同感染的人和其他动物往往会表现出食欲下降和昼夜节律行为（如睡眠）中断。这些感染对行为的一般影响被广泛地称为“疾病行为”。疾病行为对人类健康和福祉有重大影响，但对其他动物也有实际代价。例如，由于牛的感染而减少饲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。在大多数情况下，我们对它们的原因也知之甚少：免疫系统对感染产生了许多不同的信号，其中大多数信号对神经系统有影响，但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。我们在这里提出的实验集中在果蝇的两种疾病行为——减少摄食和昼夜节律紊乱。我们发现了一种特殊的基因，它在果蝇对感染的反应中被激活。这种基因产生的信号被脑细胞接收。我们发现，当果蝇受到感染时，这个信号会使果蝇吃得更少。我们在这里提出的工作的一个方面是了解感染是如何开启这个信号的，以及信号来自哪里——例如，它来自血细胞还是脑细胞？这对苍蝇来说很重要，因为不能接收到这种信号的苍蝇抵抗感染的能力就会降低；这对人类和其他哺乳动物很重要，因为我们对感染也会产生同样的信号。了解这个信号是如何产生的，是什么细胞产生的，以及它在果蝇中的功能，将有助于我们了解同样的信号在人类身上会产生什么样的变化，以及我们如何操纵这些信号来提高免疫能力或减少疾病病理。我们也想了解为什么生病时少吃是很重要的。我们的实验室之前已经证明，果蝇和人类一样，会改变它们的代谢活动来应对感染；我们最近发现，果蝇必须关闭关键的能量储存功能，以提高有效的免疫反应。关闭能量储存的一种方法是少吃。因此，我们之前的工作表明，疾病行为可能直接需要产生免疫反应。我们打算在这里做的工作将检验这一点：我们将了解减少摄食实际上对产生功能性免疫反应有多重要。这种实验在哺乳动物身上比较困难和昂贵，但在苍蝇身上相对容易和快速，它将使我们在人类和老鼠身上的实验中提出更有针对性的问题。

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.