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，通常在宿主中观察到疾病易感性的大量遗传变异。到目前为止，人们还不清楚为什么以及如何在免疫功能的遗传变异被保存在延长（即进化）的时间尺度。了解维持物种内免疫功能遗传变异的因素将告诉我们为什么选择不能消除对传染病的脆弱性，为什么某些人群比其他人群更容易感染传染病，以及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，从而影响免疫系统进化。在我们的项目中，我们将使用野生银行田鼠，一个非常听话的野生啮齿动物模型，显示了一个独特的遗传多态性在免疫受体参与防御细菌病原体，测试为什么以及如何在人群中保持免疫功能的遗传变异。寄生虫通常同时暴露于多种病原体。如果对一种病原体的抵抗是以对另一种病原体的敏感为代价的，那么这些不同的病原体群落可以维持宿主种群中的免疫基因变异。利用下一代测序技术，我们将对田鼠体内的整个微生物群落进行测序，以测试它们的基因组成是否直接或间接地通过影响它们的肠道微生物来影响病原体特异性感染。或者，免疫基因变异可能会因为抵抗力-"伤害自己"的权衡而得以维持。虽然需要强大的免疫反应来预防或清除感染，但它们可能是一把双刃剑，也会导致“自我伤害”。到目前为止，还不知道免疫基因变体在激活时引起的附带损害的数量是否不同。通过实验激活不同遗传组成的田鼠的免疫系统，我们将测试赋予病原体抗性的免疫基因变异是否也会对宿主造成更多的附带损害。最终，这些权衡可以维持免疫功能的遗传变异，因为它们确保免疫基因变异不是绝对好或坏，而是它们的成本和收益取决于宿主的外部环境或内在宿主特征，如性别。我们将通过在大型户外围栏中操纵种群密度和病原体感染风险来实验性地测试这一点，并量化具有不同遗传组成的男性和女性的生存和繁殖。这将使我们能够测试遗传变异的适应性结果是否依赖于上下文。该项目的成果将是更好地了解有助于维持自然种群免疫功能和疾病脆弱性遗传变异的机制和选择力，对进化生物学，疾病生态学，野生动物保护以及人类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.