Testing evolutionary hypotheses for the long-term maintenance of balanced immunogenetic polymorphisms in a wildlife model

传染病是人类、牲畜和野生动物发病和死亡的主要原因。虽然免疫系统已经进化为抵抗感染的防御系统，并在影响宿主健康和生存方面发挥关键作用，但它并不完美，通常在宿主之间观察到疾病脆弱性的实质性遗传差异。到目前为止，免疫功能中的遗传变异为什么以及如何在延长的(即进化的)时间尺度上保持不变还不是很清楚。了解在一个物种内维持免疫功能遗传变异的因素将告诉我们为什么对传染病的脆弱性不能通过选择来消除，为什么一些种群比其他种群更容易感染传染病，环境变化和新出现的疾病如何影响与不同免疫基因变异相关的成本和收益，从而影响免疫系统的进化。在我们的项目中，我们将使用野生银行田鼠，这是一种非常容易驯服的野生啮齿动物模型，它显示了参与抵御细菌病原体的免疫受体的独特遗传多态，以测试为什么以及如何在种群中保持免疫功能的遗传变异。寄主通常会同时接触到多种病原体。如果对一种病原体的抗药性是以易受另一种病原体为代价的，那么这些不同的病原体群落可以在宿主群体中保持免疫基因的变异。使用下一代测序技术，我们将表征田鼠体内的整个微生物群落，以测试它们的基因构成是否直接或间接地通过影响它们的共生微生物来影响病原体的特定感染。或者，由于抵抗力--“自我伤害”的权衡，免疫基因的变异可能得以维持。虽然需要强大的免疫反应来预防或清除感染，但它们可能像一把双刃剑，也会对自己造成伤害。到目前为止，还不知道免疫基因变体在被激活时造成的附带损害是否不同。通过实验激活不同基因组成的田鼠的免疫系统，我们将测试赋予病原体抵抗力的免疫基因变体是否也会对宿主造成更多的附带损害。归根结底，这些权衡可以维持免疫功能的遗传变异，因为它们确保了免疫基因变异不是绝对的好或坏，而是它们的成本和收益取决于宿主的外部环境，或者取决于宿主的内在特征，如性别。我们将通过控制大型室外围栏中的种群密度和病原体感染风险来进行实验测试，并量化具有不同基因构成的雄性和雌性的生存和繁殖。这将使我们能够测试遗传变异的适合性结果是否与背景相关。该项目的成果将是更好地理解有助于维持自然种群中免疫功能和疾病脆弱性的遗传变异的机制和选择性力量，对进化生物学、疾病生态学、野生动物保护以及人和动物健康具有广泛的跨学科影响。

Infectious diseases are a major cause of morbidity and mortality in humans, livestock and wild animals. Although the immune system has evolved as a defence against infection and plays a key role in influencing host health and survival, it is not perfect, and substantial genetic variation in disease vulnerability is typically observed among hosts. To date it is not well understood why and how genetic variation in immune function is preserved over extended (i.e. evolutionary) timescales. Understanding the factors that maintain genetic variation in immune function within a species will tell us why vulnerability to infectious diseases is not eliminated by selection, why some populations are more susceptible to infectious diseases than others, and how environmental change and newly emerging diseases influence the costs and benefits associated with different immune gene variants, and thus affect immune system evolution. In our project we will use wild bank voles, an exceptionally tractable wild rodent model that shows a distinct genetic polymorphism at an immune receptor involved in the defence against bacterial pathogens, to test why and how genetic variation in immune function is maintained in populations. Hosts are typically exposed to a wide range of pathogens simultaneously. If being resistant to one pathogen comes at the cost of being susceptible to another, these diverse pathogen communities can maintain immune gene variation in host populations. Using next-generation sequencing technology, we will characterise entire microbial communities within voles to test if their genetic makeup influences pathogen-specific infection, either directly or indirectly by affecting their commensal microbes. Alternatively, immune gene variation may be maintained because of a resistance - 'harm-to-self' trade-off. Although powerful immune responses are required to prevent or clear an infection, they may act as a double-edged sword and also cause 'harm-to-self'. To date it is not known if immune gene variants differ in the amount of collateral damage they cause when they are activated. By experimentally activating the immune system of voles that differ in their genetic makeup, we will test if immune gene variants that confer pathogen resistance also cause more collateral damage to the host. Ultimately, these trade-offs can maintain genetic variation in immune function because they ensure that immune gene variants are not absolutely good or bad, but that their costs and benefits are dependent on either the host's external environment, or on intrinsic host characteristics, such as sex. We will experimentally test this by manipulating population density and pathogen infection risk in large outdoor enclosures and quantify survival and reproduction of males and females with different genetic makeup. This will allow us to test if the fitness outcomes of genetic variants are context-dependent. The outcome of the project will be an improved understanding of the mechanisms and selective forces that contribute to the maintenance of genetic variation in immune function and disease vulnerability in natural populations, with broad cross-disciplinary implications for evolutionary biology, disease ecology, wildlife conservation, and human and animal health.