The drivers of MHC evolution during a viral pandemic

在包括人类在内的动物群体中，个体之间的免疫反应存在相当大的差异，这种差异的最重要原因之一是MHC分子，它允许免疫系统检测并对感染做出反应。MHC分子在个体之间是非常不同的，对于任何给定的感染性有机体(病原体)，一些MHC分子比其他分子更有效。然而，这种变异不仅决定了人类和其他动物能否抵御感染，还决定了他们是否会患上关节炎和哮喘等自身免疫性疾病。尽管进行了数十年的研究，但对于这些基因如何以及为什么会变得如此不同，仍有许多需要理解。研究MHC在人类、生物医学模式生物(如小鼠)和农场动物物种(如鸡)中的变异提供了许多基本信息，但许多因素使这些研究变得复杂。例如，在许多限制中，现代医学干预在人类中的可获得性很难摆脱自然选择的影响。由于MHC的变异是动物适应它们在自然界中遇到的不断变化的病原体的结果，因此研究自然种群中MHC的进化是必要的。我们最近发现，在过去70年里摧毁兔子种群的病毒性疾病粘液瘤大流行之后，兔子的MHC迅速进化，同样的变化独立发生在澳大利亚、法国和英国。我们建议利用这些自然实验来了解MHC分子的性质是如何随着动物群体对新病原体的抵抗力而变化的，以及病原体如何对抗这些防御来逃避免疫反应。这是一个了解MHC进化的独特机会，因为我们不仅可以接触到20世纪50年代和现代形式的MHC分子和病毒，而且我们在澳大利亚、法国和英国有三个独立的实验副本。首先，我们将对考古遗迹、博物馆标本和野兔的MHC基因进行测序。这将揭示MHC分子在过去5000年中是如何进化的，以及它们是如何随着粘液瘤的到来而变化的。利用这些序列，我们将研究MHC分子的性质是如何改变的。特别是，我们可以测试我们提出的一个新假设，即单一病原体的流行选择MHC分子，这些分子不仅能很好地识别该病原体，而且在细胞内高度丰富。最后，通过比较20世纪50年代和现代的病毒，我们可以测试病毒是否进化到逃避MHC分子的识别。虽然已知后一种过程发生在像HIV这样的小病毒中，但对于更大、更复杂的病毒，这一过程还不被理解。我们的研究在利用尖端技术研究免疫系统的分子功能并应用它们来理解自然生态环境中的进化方面是独一无二的。通过使用粘液瘤大流行-一个简单的自然实验重复多次-我们将获得对动物免疫系统如此可变的原因的基本见解，潜在地应用于人类生物医学、兽医和动物保护。

Within animal populations including humans, there is considerable variation between individuals in their immune responses, and among the most important causes of this variation are the MHC molecules, which allow immune systems to detect and respond to infection. MHC molecules are extremely variable between individuals, and for any given infectious organism (pathogen), some MHC molecules are more efficient than others. However, this variation not only determines whether humans and other animals can defend themselves against infection, but also whether they develop autoimmune disorders such as arthritis and asthma. Despite decades of research, there is still much to understand about how and why these genes become so variable. Studying MHC variation in humans, biomedical model organisms such as mice, and in farm animal species such as chickens has provided much fundamental information, but many factors complicate such studies. For instance, among a number of limitations, the availability of modern medical interventions in humans is difficult to disentangle from the effects of natural selection. Because MHC variation is a consequence of animals adapting to the ever-changing array of pathogens that they encounter in nature, it is essential to study MHC evolution in natural populations.We recently found that the MHC of rabbits evolved rapidly after the pandemic of the viral disease myxomatosis that has devastated rabbit populations over the last 70 years, with the same changes occurring independently in Australia, France and the UK. We propose to use these natural experiments to understand both how the properties of MHC molecules change as an animal population evolves resistance to a new pathogen, and how the pathogen counters these defences to escape the immune response. This is a unique opportunity to understand MHC evolution as not only do we have access to the 1950s and modern forms of both the MHC molecules and the virus, but we have three independent replications of the experiment in Australia, France and the UK. First, we will sequence the MHC genes from archaeological remains, museum specimens and wild rabbits. This will reveal how MHC molecules evolved over the last 5000 years, and how they changed with the arrival of myxomatosis. Using these sequences, we will then investigate how the properties of the MHC molecules have changed. In particular we can test a new hypothesis we have proposed, that epidemics of a single pathogen select for MHC molecules that not only recognise that pathogen very well but are also highly abundant within cells. Finally, by comparing 1950s and modern viruses, we can test whether the virus has evolved to escape recognition by MHC molecules. While this latter process is known to occur in small viruses like HIV, this process is not understood for larger more complex viruses. Our study is unique in utilising cutting-edge technologies for studying the molecular functioning of immune systems and applying them to understand evolution in a natural ecological setting. By using the myxomatosis pandemic-a simple natural experiment replicated several times-we will gain fundamental insights into the reasons why animal immune systems are so variable, with potential application to human biomedicine, veterinary medicine and conservation.