Host-Pathogen Interactions as a Resource-Competition Problem

营养不良和肥胖是当今世界影响人类的两种最普遍的营养状况。除了对身体状况和总体健康的明显病理影响外，患者还可能降低抵抗感染的能力。有鉴于此，医疗机构（如铁和维生素补充剂）和医疗边缘都越来越多地使用旨在增强免疫力的营养补充剂。虽然毫无疑问，某些关键营养素在对抗感染方面发挥着重要作用，但迄今为止，许多研究都是孤立地对单一营养素进行的，没有考虑它们如何与饮食中的其他成分相互作用，也没有一个强大的框架来评估它们的功效或作用机制。当前提案的目的是将营养生物学、生态免疫学和群落生态学提供的理论联合收割机结合起来，以开发一个新的框架，使我们能够测试有关营养在决定感染结果方面的重要性的想法。昆虫及其病原体可以为了解人类疾病提供有用的模型。这是因为昆虫相对简单的免疫系统与人类的先天免疫系统有着惊人的相似之处。此外，昆虫往往比人类更容易工作，但表现出许多相同的营养行为，如肥胖，厌食和自我药疗。我们将使用毛虫，Spodoptera littoralis，和细菌，枯草芽孢杆菌，作为模型系统，探索大量营养素对先天免疫和病原体抗性的影响。我们以前的研究表明，健康的昆虫在蛋白质（P）和碳水化合物（C）的相对量大致平衡的饮食中表现最好，这是昆虫最重要的两种宏量营养素。如果昆虫吃太多或太少的P或C，那么它的表现就不那么好，这表明这是未感染时的“最佳”饮食。相反，感染了病原体的昆虫，如B。枯草芽孢杆菌，如果它们吃的是富含蛋白质的食物，存活率会高得多。此外，如果给它们选择，受感染的昆虫将以高蛋白质含量的食物为食，以帮助它们生存。我们将使用逐步实验方法来确定我们是否可以通过了解宿主和病原体在隔离生长时的情况来预测病原体感染的结果。特别是，我们将检验零假设，即感染的结果（例如昆虫的生存或死亡）仅由宿主和病原体的营养需求决定。我们将使用20种不同的人工饲料，它们的P：C组成各不相同，这样我们就可以迫使昆虫摄入不同数量的P和C。1.我们将从确定昆虫的饮食如何影响其血液的营养成分开始，这是细菌将喂养的地方。2.然后，我们将在一系列肉汤中培养细菌，这些肉汤与每种饮食中的昆虫血液具有相同的营养成分，但没有血细胞和其他免疫防御。这将向我们展示在没有宿主的情况下细菌的营养需求。3.然后，我们将确定昆虫宿主的免疫防御如何在没有病原体的情况下通过向昆虫注射死细菌来刺激免疫反应来执行，我们将使用遗传和其他方法对其进行量化。前三个实验将使我们能够确定宿主（昆虫）和病原体（细菌）在不同饮食中的表现如何不同，并根据谁控制营养使用的假设来预测赢家和输家。4.最后，我们将用活细菌注射毛毛虫，并量化细菌生长速率和昆虫生长/存活率的结果，使我们能够测试这些预测。

Malnutrition and obesity are two of the most prevalent nutritional conditions affecting humans around the world today. As well as their obvious pathological effects on body condition and general well-being, sufferers may also have a reduced capacity to resist infections. In light of this, there has been a growth in the use of nutritional supplements aimed at boosting immunity, practiced both by the medical establishment (e.g. iron and vitamin supplements) and on the medical fringes. Whilst there is little doubt that certain key nutrients can play an important role in fighting infections, many of the studies to date have been conducted on single nutrients in isolation, without considering how they interact with other components of the diet, and without a robust framework for assessing their efficacy or mechanisms of action. The aim of the current proposal is to combine the theories provided by nutritional biology, ecological immunology and community ecology to develop a new framework that will allow us to test ideas about the importance of nutrition in determining the outcome of infections. Insects and their pathogens can provide useful models for understanding human diseases. This is because the insect's relatively simple immune system shows striking parallels with the human innate immune system. Moreover, insects are often easier to work with than humans, yet exhibit many of the same nutritional behaviours, such as obesity, anorexia and self-medication. We will use the caterpillar, Spodoptera littoralis, and the bacterium, Bacillus subtilis, as a model system for exploring the effects of macronutrients on innate immunity and pathogen resistance. Our previous studies have shown that healthy insects perform best on a diet that is roughly balanced in terms the relative amounts of protein (P) and carbohydrate (C), the two most important macronutrients for insects. If the insect eats too much or too little P or C, then it performs less well, indicating that this is the 'optimal' diet when uninfected. In contrast, insects that have been infected with pathogens, like B. subtilis, have much higher survival rates if they eat a diet extremely rich in protein. Moreover, if they are given a choice, infected insects will feed on a diet with a high protein content to aid their survival. We will use a step-wise experimental approach to determine whether we can predict the outcome of pathogen infections by understanding how the host and pathogen fare when grown in isolation. In particular, we will test the null hypothesis that the outcome of the infection (e.g. whether the insect lives or dies) is determined solely by the nutritional requirements of the host and pathogen. We will use 20 different artificial diets that vary in their P:C composition, so that we force the insects to ingest different amounts of P and C. 1. We will start by establishing how the diet of the insect affects the nutritional composition of its blood, which is where the bacteria will feed. 2. We will then grow the bacteria in a range of broths that have the same nutritional composition as the insect blood on each diet, but without blood cells and other immune defences. This will show us the nutritional requirements of the bacterium in the absence of the host. 3. We will then determine how the insect host's immune defences perform in the absence of the pathogen by injecting the insect with dead bacteria to stimulate the immune response, which we will be quantified using genetic and other methods. These first three experiments will allow us to determine how the performance of the host (insect) and pathogen (bacteria) differs on different diets and to make predictions about winners and losers based on assumptions about who controls nutrient use. 4. Finally, we will inject caterpillars with live bacteria and quantify the outcome in terms of bacterial growth rates and insect growth/survival, allowing us to test these predictions.